Hey, buddy. I thought it's 1045, so we should start on time so we can finish on time. I'm Sumit Bhargava. I'm the chair of this session. This is the Pediatric Year in Review and Transition of Care session. We are all grateful you are here today. Our first speaker is going to be Dr. Adam Shapiro, who is a pediatric respirologist from McGill University. He also serves as the medical director of the PCD Foundation Clinical and Research Center Network, which is an organization based both in Canada and the United States. So I think it's fair to say that Dr. Shapiro has been working on bronchiectasis for a very long time. And this is actually what he is going to be talking to us about. Dr. Shapiro. Thank you so much. Can everyone hear me OK? Good? OK, great. So here's my disclosure slide, as you can see. And you can read the objectives. We're going to talk about what's gone on in the last year in PCD and non-CF bronchiectasis. And so PCD is a chronic respiratory disease where there's defective mucus clearance from the upper and lower airways. And it's from a genetic origin, as opposed to secondary ciliary dyskinesia. If you come visit me in Montreal in February and your cilia are paralyzed from the cold, your nose will run. That's not what we're talking about here. And the cilia are dysmotile and stiff. They're not completely immotile. And you develop chronic ear, sinus, and pulmonary disease with resulting damage. And there are multiple different aspects of the cilia that can be poorly constructed due to a genetic basis that can cause PCD. And again, you have this classic 9 plus 2 organization that you saw one day in embryology in your first year of medical school and never thought you would see again. And it's back. But we'll go on. So as far as we know, the vast majority of PCD is autosomal recessive. And it used to be thought to be a rare disease, 1 in 15 to 1 in 30,000. Depending on how you calculate the population of North America, if you put Mexico in or not, that means there's over 40,000 cases and less than 1,000 are definitively diagnosed. And we know that there are higher rates in closed or consanguineous populations, including all of those that I've listed here. But also South Asians in Great Britain can have a prevalence of 1 in 2,000, which is as common as cystic fibrosis. But in the past couple of years, there's been a very nice genetic approach to prevalence prediction done using 29 of the 50 known PCD genes or greater than 50 known genes. And what they showed that the prevalence is probably at least 1 in 7,500, which means it's nowhere near as rare as we thought it was. And there's also a predominance in African or African-Americans, 1 in about 10,000, which we are not picking up in any of our clinical registries. They're grossly underrepresented of that ethnicity or that origin. We also know that if you look closely at other closed populations, such as our indigenous populations around the world, bronchiectasis is a massive problem. And you'll see that as a recurring theme. It's about 200 times higher in Canadian Inuit children than it is in white children. And no one knew why, and everyone wondered, was there PCD? And it turns out, if you look closely, there's a lot of PCD. So we've now found more than nine cases of PCD in our Canadian Inuit, all caused by a similar mutation, the same mutation of DNA H11, which gives them normal electron microscopy. And that's why they've been missed for so long. And this sets the relative prevalence of PCD in the Canadian Inuit population of 1 in 1,400, with a carrier rate of at least 1 in 19, which is much higher than the F508 rate in whites. So newborn screening should be coming. But we have also found this in other indigenous populations, such as the First Nations populations, which were across the Great Lakes and throughout Canada and the US, caused by a completely different mutation in DNA L1. So very highly ladened recessive diseases in some of these populations, causing a lot of bronchiectasis when you look. Now as far as diagnosing PCD, we know there's no single diagnostic test that will pick up all forms. And that's the biggest problem. There are five main tests, with many being absolutely impossible to do outside of world expert centers. And when I say world expert, I mean two to three centers across the entire world. What the ATS recommends is nasal nitric oxide testing in people above five years of age, and or genetic testing, with the other tests more falling to the wayside because they're difficult to do. And in 2007, there were nine known PCD genes. Now there's over 50. I think we're at 54 genes. So you can see in comparison to CFTR in the pink, with 27 exons, it's taken us 40 years to learn about. There's a heck of a lot more coding regions to go through in all of the PCD genes combined. We also know that you can have intronic variants causing this that will be completely missed on whole exome sequencing. And a lot of them happen with deletion duplication as well. So if we look at how the genetics affect the ciliary ultrastructure, you can see on the left are the ones with classic transmission electron microscopy defects. In the middle are non-classic defects. And at this other side are normal, completely normal electron microscopy. And if you look at blue, those are all the new genes that have just been discovered in the last year. So it continues to evolve. And you can't use genetics as a rule-out test because your patient could have a gene that's not been discovered yet. But we also know there's five main genes. You can see them in red that account for about 40% of PCD. But overall, we can only detect about 70% to 80% by genetics. And we've all been wondering, well, what is the big gene we're missing that accounts for that other 10% to 20%? And it turns out it's called the Haydn gene. So Haydn is a rare gene that was only thought to occur in the Faroe Islands halfway between Iceland and Denmark. And it's a large gene. So most places don't want to deal with it, 86 exons. There's a pseudogene on chromosome 1 called Haydn 2, which takes an additional step of if you find a change, you have to map it to Haydn or Haydn 2. So again, most people don't want to deal with it. And it's not in most genetic panels. And it actually encodes for the C2b projection, which you can see over on the right of the central apparatus. And unfortunately, standard electron microscopy is not good enough to see that. The other problem is they have no laterality defects. So their organs are normally placed. So they're very, very hard to detect. But what we did was look back at our institution and looked at roughly 21 families that we knew had PCD but were unable to diagnose. And when we checked the Haydn genes, about 30% of them had Haydn. So overall, that's about 9% to 10%. And this has been corroborated in Europe now. So if you have a patient with normal organ situs that you really think has PCD but you can't prove it, they likely carry the Haydn gene. And you have to find a way to test that. Looking at our other test, which the ATS recommends, nasal nitric oxide, what we see is now there's a lot more genes that can have normal nasal NL. And you can see all the red ones here. So in 2013, nasal nitric oxide was highly sensitive and specific for a diagnosis of PCD. But since we've discovered a lot more genes resulting in normal ultrastructure, that sensitivity and specificity has dropped, although it's still pretty good at 92% and 86%. And it's better if you actually have abnormal electron microscopy. So the bottom line for this other recommended test is it's not a rule-out test. It's not a sweat test. It can send you in the right direction. But it can't tell you for certain that your patient doesn't have PCD. We're starting to learn a little bit more about the genotype-phenotype relationships. And we've known for about a decade now that if patients that have variants in the CCDC39 or CCDC40 genes or the corresponding interdining arm defect with microtubular disorganization, they have worse outcomes. They have lower baseline FEV1 to start with. They have low BMI. And we don't know why, because there is not a malabsorptive component to this, like CF. They have a faster decline in FEV1. And Bree Kinghorn's group in the GDMCC has recently shown us that they also have much worse CT outcomes with more mucus plugging and more percent of their lungs affected. And the reason for this is unknown. Everyone's trying to figure out why this specific genotype is worse. And when we actually look at the mucus and the inflammatory substances in the sputum from these patients, they're no different from other PCD patients. And Scott Sagel and his group showed that. But Carlos Mila from Stanford recently looked at basal cells and multiciliated epithelial cells in patients with CCDC39, one of the severe genes, and the two other more common genes. And he showed that not only at a cellular level is there higher inflammatory profiles in these genes, in cells with these genes, but they also have a much higher and more robust inflammatory response when stimulated. And you can see both TNF-alpha, MCP, CCL2, and IL-6 are all elevated in the stimulated CCDC39 cells versus others. So we also thought there were mild variants, and we thought there were mild genes. And one of them was RSPH1, which in 2014 was shown to have better outcomes, overall better lung function, a bit of a later onset in their cough, and things like that. But we now know that's not true. This was a recent reanalysis of that data presented at the World Bronchiectasis Day Conference that showed that RSPH1 is not worse than the most common PCD gene, DNH5. But the other radial spokehead proteins, which mainly include RSPH4A, which is a very large founder gene in the Puerto Rican population, but also outside of Puerto Rico, they seem to be worse. And what was very interesting for the first time is they looked at the type of variant in the gene. So there's loss-of-function variants, where you get almost no protein made. And then there's missense variants, where you might get some protein made. And it turns out those actually have an impact. So in females, and I don't know why it might have just worked out that way, versus males, two loss-of-function variants gives you a much worse outcome than two non-loss-of-function variants. And this has been recapitulated in mouse models with the DNAF5 variant as well. So it's probably not just the actual gene you have, but it might be the type of change within the coding region of that gene that makes you worse. We finally have some data on things that we take for granted in cystic fibrosis, such as pseudomonas. So this report, this series out of the Toronto Hospital for Sick Children, showed us that in patients with PCD and pseudomonas infections, about 97% can be cleared with one or two months of inhaled, if they're asymptomatic, inhaled tobramycin, and then followed by an IV eradication protocol. And reinfection occurs in roughly one-third within the next year. So we finally are starting to realize we can get rid of pseudomonas, and it goes pretty well in most children. And then one of the biggest things to come out this year is the second ever RCT in PCD, which was a multinational inhaled ENAC study of 123 patients. And the thought is that it's not just a motility problem of the cilia. There actually is a dehydration of the mucus with increased mucin content. And this was a crossover study looking at idrevleride with or without hypertonic saline and placebo. And it actually showed with just the idrevleride and hypertonic saline, there was a nice but small increase over 28 days. There was an extension where you could add ivacaftorin, which didn't work. But it showed that during that extension period, the effect of the idrevleride and hypertonic saline increased and was prolonged and had about a 5% increase overall in FEV1. This was a phase 2 study with phase 3 coming soon. And on the horizon, there are two companies working on inhaled mRNA. And I actually think PCD will be the first disease to have inhaled mRNA. One is working on the DNAI1 gene. The other is working on CCDC39. And their preclinical studies have shown that they incorporate well into the gene that they make, excuse me, into the cell. They make the protein. And the effects are sustained for about four weeks. And phase 1 studies are now going on in Australia and New Zealand. So just to shift in the last few minutes that I have to non-CF bronchiectasis, many of us use azithromycin in non-CF bronchiectasis. We use it in PCD as well. It's been proven to work. But we often get the question, how long do you use it for? When do you stop it? And this is actually a reanalysis by the group from Australia looking at a two-year study of high doses of azithromycin once weekly in an indigenous population. And what they found was the most effective times for decreasing exacerbations was between 17 and 62 weeks, which for me means that if it takes about four months to really start to have an effect, a six-month trial may be a little short. And you may want to go to an actual 12 months. So we actually have some data to support this now. And then lastly, we're starting to look at this big grab bag of non-CF bronchiectasis and try and figure out what are the endotypes and the phenotypes and the genotypes that separate these people because they're all very different. And this is a big study from Dr. Chalmers' group in the UK that basically looked at 199 stable active non-CF bronchiectasis patients, followed them for 12 months, used a cluster analysis to classify them per their inflammatory markers. And what they showed was those with mixed neutrophilic and T2 inflammation and those with more severe neutrophilic inflammation. And you can see on this graph down at the bottom, clusters two and three had a much higher rate of exacerbation over the 12 months following, and they had reduced diversity of their microbiome, meaning they had a lot more pseudomonas, a lot more haemophilus, and that seems to be a bad thing. So this is going to be critical for actually targeting these people in the future for studies where you're looking at outcomes and agents. You have a lot of different types of bronchiectasis you can enroll. And then lastly, in my last one minute, I was asked to talk about transition. So there are two retrospective studies on transition in non-CF bronchiectasis. Both involve indigenous populations, both in Australia and in Alaska. And basically what they showed was even though these kids are plugged in really well in the pediatric period, once they get to the adult side, they're completely lost. They never see a respirologist or a pulmonologist, excuse me. There's no planning for transition whatsoever, even in some of the best bronchiectasis clinics in the world. And again, when they make it to adulthood, less than 5% are actually seen by adult pulmonologists. So we are doing abysmal on transition. A lot of it has to do with the remote location of these patients, but that's where your worst bronchiectatics are in your indigenous populations. They don't live near large population centers. And then lastly, transition in PCD. I searched PubMed. You get one article that really doesn't even talk much about transition. It's a review, but the word transition appears in the keyword. That's it. Sad. So the problem is we haven't really had a place to send these kids. I find a lot of our adult providers don't really ask why they have PCD or why they have bronchiectasis. They don't really care that they have PCD because they say, we don't have disease-specific therapies. But the only way we're going to change that is to actually diagnose it and make adult centers to follow these kids in, like we did in CF 40 years ago. So the PCD Foundation realized this in the last couple of years. And you can see our extensive CRCN network. And you can see all the ones in red are actually adult-accredited centers where we can now send these kids in transition. So that's my talk. I'll leave the summary for you to read. And I don't want to go over time. Thank you. Thank you. Well, that was just an excellent talk, Dr. Shapiro. I think we are going to reserve questions for the end just because we want our speakers to get through this great information that they're going to be sharing with you. So our next speaker is going to be Dr. Manindar Kalra. He is an associate professor of pediatrics at Ohio State University. He's the medical director of the Sleep Medicine Laboratory at Nationwide Children's Hospital. His research is focused on using artificial intelligence analytic tools to better define disease phenotypes and to quantify the impact of sleep disorders on respiratory disease outcomes. He also serves on the Artificial Intelligence Committee of the AASM. He's going to be talking to us today about something that is a little different than artificial intelligence. He's actually going to be talking to us about technology-dependent children, non-invasive and invasive ventilation. Good morning, everyone. Thank you, Dr. Bhargava, for the invitation. I have no disclosures pertaining to this talk. The objectives of my talk today are to review advances in positive airway pressure therapy in children, to discuss the role for volume-averaged positive pressure support in non-invasive and invasive ventilation, and to evaluate the impact of WAPS therapy on adherence in children. Respiratory failure, which is defined as the inability of the respiratory system to maintain oxygenation and adequate ventilation when it is chronic, can be empirically divided into three stages. Stage one, when you have intermittent hypoxemia and hypercapnia, which is limited only to REM sleep. And stage two, when the hypoventilation extends to both REM and non-REM sleep. And stage three, when the hypoventilation is present both during sleep and wakefulness. When we look at initiatives to mitigate the inadequate ventilation, it's important to remember that our efforts to improve the lung volume, as well as provide additional respiratory rate support, also help the upper airway by splinting the airway and decrease the airway collapsibility due to the increased tug from the increased lung volume. PAP therapy has been shown to be efficacious in children. Whether they are adherent to this therapy is not well understood. So this study from Bhattacharjee and colleagues looked at over 20,000 children in North America on PAP therapy, on which 90 days of compliance data was available. And they wanted to answer the question about adherence, as well as identify clinically actionable items that could improve adherence. And they were able to report overall 60% compliance with PAP in children, and in this large cohort of over 20,000 children, 12,000 were using PAP. And they also identified that age group 6 to 12, as well as participation in a patient education program, and reduced mask leak, and optimal pressure, and finally reduced residual AHI were associated with adherence to PAP. Volume-assured pressure support is a relatively newer mode of ventilation, which has been designed to deliver a set target volume or ventilation by varying the level of pressure support. And you can, there are two common modes of this ventilation available. One, the average volume-assured pressure support, which targets the alveolar volume, tidal volume, and the intelligent VAPs, which targets the alveolar ventilation. And you can, by setting some bounds on the inspiratory pressure support, you can deliver a set target volume or ventilation. And as you can see listed on the left-hand side of the slide, the conventional modes of fixed bi-level positive support, they do not respond to changes in tidal volume needs with change in position or sleep stages. And VAPs, by able to successively deliver the target, is well-suited to fixing the changes in tidal volume needs, both with position as well as sleep stages. And Diaz and colleagues have reported a case series. And this is an 8-year-old child with severe obstructive sleep apnea. And the slide shows the baseline sleep study variables. The first column is showing a severe obstructive sleep apnea with apnea hypopnea index of 138 episodes per hour, and severe desaturations down to 59%. CPAP titration to up to CPAP of 19 centimeter water did not result in resolution of sleep apnea. And this is a patient who otherwise would have met criteria for tracheotomy, but was successfully managed with AWAPS auto-adjusting EPAP, where you can see the results of the titration study in the last column, where the apnea hypopnea index and the oxygenation improved significantly as compared to continuous positive airway pressure alone. Children with neuromuscular disease do require chronic ventilation and non-invasive being our preferred mode. And the question is, can this new mode of ventilation in children improve overnight adherence, which continues to be an issue in this group of patients? And this study shows it was a prospective observational study in 20 children with neuromuscular disease at a center, where they compared the adherence data for BiPAP ST with WAPS mode. And as you can see, the adherence was 87% for BiPAP ST and 100% for WAPS over a period of 90 days. There was no difference in gas exchange parameters on the polysomnography between the two modes of ventilation. This methodology of assured volume support has also been used in infants. This is a case report from Children's Sydney, where Sadi and colleagues used AWAPS in an infant with severe BPD and chronic respiratory failure. And the top graph shows that despite adequate oxygenation, CO2 was not adequately controlled. The lower data trends on oxygen and CO2 are significantly improved, especially for the CO2 trends, where you see the mean TCO2 is much lower on AWAPS therapy. Congenital central hypoventilation syndrome is a rare disorder where you have defect in alveolar ventilation, as well as autonomic dysregulation due to genetic mutation in the FOX2B gene. And the hypoventilation is worse in non-REM sleep, and there is a further reduction in tidal volume overall in sleep. So children with this condition require varying levels of support, depending on the sleep stage, REM versus non-REM. And that's where volume-assured pressure support has a role. And this is, again, a study case report from Sadi and colleagues from Children's Sydney and University of New South Wales, where the top graph shows a TCO2 trend on the infant, a 10-month-old infant who is on BiPAP ST support. And you can see the cyclic oscillations in transcutaneous CO2 between 35- and 45-millimeter mercury. And the mechanism of these oscillations is not known. However, it could be due to the abnormal chemoreceptor control and the delay in acid-base response, or it could be the change in ventilatory response to being on BiPAP ST mode. The lower graph shows that when you initiate AWAPS therapy in this infant, these oscillations in transcutaneous CO2 are lost, thereby supporting use of WAPS mode of ventilation in this group of children. So far, we have reviewed the application of WAPS therapy to several disease groups in the non-invasive mode. And the group from Vanderbilt reported their experience on 77 children who were getting this mode of ventilation via tracheostomy. And in their cohort, they have split the patients based on the indication for tracheotomy and invasive ventilation. And the children with WAPS were more likely to be selected to that group if either the upper airway lesion that indicated the tracheostomy was known, or the indication was just to provide access for support, such as in a child with BPD. And as you can see, there were some differences. Overall, this group has a 50% readmission rate after tracheotomy. Children with WAPS were younger, and that may explain the extended length of stay in this group of patients. Because if you are going to select in your cohort younger children with BPD who are going to get tracheostomy, they are obviously going to stay longer, as opposed to stable children with complex conditions needing tracheostomy, which was in the no AWAPS group. And that's why the difference in decannulation rate, where they did not have any decannulation in the AWAPS group. BPD was reported in children, a higher rate in children who did not go on AWAPS. And that most likely is due to more complex cases getting onto that group. So this group demonstrated that AWAPS mode can be used to deliver invasive ventilation in children, too, as has been demonstrated in adults. So far, we've reviewed that this relatively new mode of ventilation can be used to deliver positive pressure therapy in children, and both in the invasive and non-invasive ventilation. There is several case reports on the use of WAPS in children. And there is a need for prospective and randomized control studies, which involve multiple centers. And there is a potential for WAPS to improve adherence to therapy, based on what we know are predictors to adherence, as well as in the study we reviewed in children with neuromuscular disease, which clearly showed that children on WAPS did better than bypass ST. Thank you. I'll stop here. Thank you very much, Dr. Khandra. I would like to now introduce our next speaker, and that is actually Dr. Courtney Gushue, who is Assistant Professor of Pediatrics at Nationwide Children's Ohio State University. She is a busy clinician with clinical interests in neuromuscular disease, cystic fibrosis, and sickle cell lung disease, and is involved in research in all of these areas. And today, she is specifically going to be talking to us about bronchopulmonary dysplasia, and how bronchopulmonary dysplasia is essentially a disease that is very much appropriate for transition to adult care. Dr. Gushue. Thank you, Dr. Bhargava. Thanks, everyone, for coming today. OK. So my objectives for the talk today, we're going to talk about the evolution of BPD from its initial description back in the 60s to current day. We're going to understand some of the important outcomes and comorbidities in this population, and really talk about some of the unique challenges in the role of transition from neonatal care to pediatric care on to adult care in this population. So first, to get a little background on BPD, we need to think about sort of the many different definitions that we can use to define BPD. There's a lot of different evolving definitions based on different levels of oxygen support at different times post-gestational age. But really the important thing to note is that it's this chronic lung disease related to prematurity. And you can see on the right here, there's a lot of different features, including lots of inflammation, reduced vascularization, and different types of trauma that can lead to lung disease here. So we know several infants are affected by this, and almost 50% of infants born less than 29 weeks of estimated gestational age are gonna develop bronchopulmonary dysplasia. This population's really growing lately, and we have increasing technologies. People are living at younger gestational ages now, and ultimately we're leading to a larger population and even more people that are growing to be adult survivors of BPD that need to have adult pulmonologists. So currently there's an incidence of about 50,000 new cases of BPD per year in this country. And we'll go on to talk about some of these unique challenges. You really can't talk about BPD without talking about Dr. Northway back in 1967 when he first described this disease. And really what he sought to investigate further was what's this new chronic pulmonary syndrome? So he saw that there was new disease, and this was happening in patients who were requiring what he called high oxygen, so FiO2s of 80 to 100%, or chronic need for mechanical ventilation after the first six days of life. And what we saw back in the 60s is this sort of evolution of disease. You can see the three images on the right. On the left side there is sort of initial chest X-ray at birth with what we usually see as RDS, or respiratory distress syndrome, sort of evolving into an ARDS picture on the top of the screen, and ultimately resulting in this chronic disease with hyperinflation and lots of sort of cystic changes and phrebotic changes. When he was looking at infants in his era, we were seeing more of these patients around 35, 34 weeks of estimated gestational age, which is a lot older than the infants that we're seeing now in our new BPD. They were weighing just over two kilos and had almost a 70% mortality back in the 60s. And ultimately, and unfortunately, what we saw was that based on a lot of postmortem exams, he came up with this term of bronchopulmonary dysplasia based on the appearance of the airways and the abnormal parenchyma in this population, and really saw these three main pathogenic factors, which were lung immaturity, acute lung injury, and ultimately an inadequate repair of this initial injury. And these are important to note because they're things that we really think about still today when we look at BPD and sort of how we need to approach it, try to prevent it, and ultimately treat it. So again, a lot of people have probably seen a slide similar to this in the past if you've gone to other BPD talks, but we really think about in the last few decades just this old BPD versus new BPD. And one of the big factors that accounts for the changes in this old versus new BPD is the advent of giving surfactants. So the pre-surfactant era, really before 1980, is when we're seeing more of this old BPD. And that's gonna be your images on the left side here. So that's your classic or old. You can see in the chest X-ray here, there's certainly scattered areas where you have more atelectasis in the right upper lobe here, significant hyperinflation and downward displacement of the diaphragm, and lots of cystic and fibrotic changes. Some of the really important things to note that in old BPD, there was really significant smooth muscle hyperplasia and this fibroproliferation leading to chronic lung disease. And then when we think about our new BPD or more recently, you can see the pattern in the X-ray here is a lot less heterogeneous there, so it looks more like kind of a early-onset RDS. And this big focus on what we call alveolar simplification is what we focus on in BPD now. And that's really where we have this decreased septation and the dysmorphic pulmonary microvascular growth, ultimately leading to fewer alveoli and they're of a larger size leading to decreased surface area for gas exchange. So shifting from sort of this last few decades of how we've thought new and old BPD was some differences is really thinking about what's changed in the last couple of years. And quite honestly, there's not been a ton of advances, but we'll think about things first as far as diagnostics go. There's been sort of a hot topic in the neonatology world of lung ultrasound and point-of-care ultrasound in the NICU. So in pediatric pulmonology last year, one of the highest cited submissions for articles in the neonatal section was on lung ultrasound. And I have to admit, as I'm talking about it, I'm no expert and I can't claim to read lung ultrasounds, but neonatologists are really focusing on training their fellows and their current faculty to be able to use this so that they can have more real-time information, they can gain data more rapidly than waiting for things like x-ray and ultimately trying to minimize the amount of radiation to their patients. So there's some utility in the neonatal world in using point-of-care ultrasound to try and diagnose things like pneumothorax and proper placement of endotracheal tube, again, without having to wait for arrival of x-rays. And then there's also some recent updates in lung ultrasound and looking at these new lung ultrasound scores. And over the last couple of years, they've been able to correlate some higher scores based on looking at six areas of the chest with point-of-care ultrasound and really making some clinical correlations with certain disease processes. So things like respiratory distress syndrome, transient tachypnea of the newborn, and even being able to use it as predictors for need for CPAP, need for surfactant, and ultimately the development of BPD. And I think this area can be really useful in the coming years as we get more comfortable and more familiar with using the lung ultrasound. In research, if we're gonna try and prevent BPD, we know those are gonna be at higher risk of it based on lung ultrasound scores that can be used in future research. As far as treatments in BPD go, there's, again, unfortunately, not a lot of new therapies out in the last couple of years. But some of the things that we'll talk about are ventilation strategies. As Dr. Kalra mentioned, there's certainly some talk on using things like AVAPs in this population, which hasn't previously be done. And I believe there's a talk later in this week specifically talking about AVAPs in the BPD population. We know generally with severe BPD, we're gonna think about using sort of a different approach in our ventilation strategies. So we think about using a low respiratory rate, a longer eye time, and higher tidal volumes for theoretically trying to ventilate better all of the areas that have different areas of compliance in the lung and allowing for enough time for full exhalation there. Of course, surfactant is one of the mainstays of treatment and prematurity. There hasn't been a lot of changes there. And we know, again, post-1980, we see a lot different picture of BPD after surfactant was introduced. Caffeine's another one of the mainstays that we'll see used in the NICU. There's certainly studies that show benefits of using caffeine in this population. There's a reduced incidence of BPD when we use caffeine, although the mechanisms are not very well understood. Yuan and colleagues last in 2022 published in Pediatric Pulmonology to try and identify some of the mechanisms more so and had a lot of proposed mechanisms of decreased inflammation in the lungs when we used caffeine. There's a lot of debate still out with the rest of the treatments for BPD. And if you guys recognize generally in your different NICUs and pulmonary clinics, you might see that there's some differing opinions even within your institutions. So diuretics, we know, can have an acute effect, improve your lung compliance acutely, but there's not a lot of great long-term data on BPD outcomes in diuretics. We know there's certainly risk factors with nephrocalcinosis and metabolic derangements. And then steroid use, of course, is another hot topic of debate in BPD. So we know that there are certainly poor neurodevelopmental outcomes when we use steroids in this population, but there's certainly acute improvements in lung function as well. There's some newer research and ongoing studies currently looking at budesonide and surfactant used together in hopes to limit the systemic effects of steroids in this population. So I think there will be more to come in the next few years about the use of these therapies. We know, and particularly on the pulmonary side of things, that we use a lot of bronchodilators in these patients. There's not great data to say when and how long we should use these, but we know there's a clinical impact based on their airway hyperactivity. In recent years, there's been some investigational therapies ongoing. Unfortunately, like I said, not a solid new therapy, but I think some interesting things to think about, one of these being vascular endothelial growth factor. And so when we think about the development of the lung and the airways, we know that airways are going to develop alongside our blood vessels. So if we could, in theory, improve our vascular growth with VEGF, we could better alveolarize. However, there were studies looking at BPD models of mice, and there's actually seen to have overexpression of VEGF leading to alveolar capillary membrane disruption and also alveolar simplification, which are both what we're trying to avoid here. Other recently kind of hot topics are mesenchymal stem cells and you can see the larger graphic here looking at a lot of the different inflammatory pathways. So again, I think in the coming years, there's going to be more data coming out, some early trials and animal models looking at mesenchymal stem cells and how they can switch macrophage types and alveolar type one and two cells and their inflammatory effects in the airways. So more to come on that, but currently no approved therapies here. So without any major new treatments, we're sort of stuck dealing with the consequences of BPD. We know a lot of information about the childhood consequences of BPD, knowing that generally half of these kids are going to be hospitalized in their first two years of life, most often because of RSV infections, which is why we talk so much about RSV prophylaxis. And then we know a lot about their lung function as we've studied over the years that they're certainly set up to have reduced lung functions and really not meet normal lung function and go into adulthood with a lower reserve. So the graph that's listed here is your x-axis is age four through 12, and this is looking at PPFEV1Z scores and those with BPD versus no BPD. So your solid blue line is BPD and your dashed blue line is no BPD. And you can see there's really a significant drop in lung function just over a matter of eight years before you even reach adolescence. So they're really starting at a disadvantage going into adulthood. We know some of the symptoms they have are exercise intolerance, asthma, bronchodilator response, and certainly pulmonary hypertension and some of the other non-pulmonary complications. And these transition over into adulthood too. So as we're having more adults living into older years who've survived BPD, we're learning a lot more. I think one of the things, a caveat to note, that a lot of what we know so far is adults who've survived from sort of old BPD when we think about when surfactant was introduced right in 1980. So we have a lot of research to go moving forward in some of our younger adults and how the new BPD is looking in the adult population. We know some of the same lung function and symptoms are gonna persist into adulthood here. You can see there's even some radiographic changes that persist into adulthood. So the image here on the right side is from an adult 25-year-old who was a 29-weeker, just requiring oxygen for two months of life. It's not showing up super on the screen here, but you have an inspiratory A image and an expiratory B image. And you can see there's some emphysematous changes and some air trapping that are worse on exhalation here, persisting all the way into the 20s. We're seeing a lot more data showing that these folks are looking more like COPD or a COPD-like syndrome, both in their symptoms and some of their radiographic findings and also some of their cellular findings like increased CD8 and reduced CD4 cells. So this information can help us hopefully get some more information and more therapeutics down the road. So again, some of the phenotypes that we can see in BPD are this asthma-like, emphysematous, and pulmonary hypertensive phenotypes. I'm not gonna go into detail on all of these, but Cassidy had a really nice paper a couple years ago in CHESS that outlined these phenotypes. This just sort of highlights the importance, again, some of the things we've already talked about are in this slide that I won't go into detail, but really thinking how many changes we know happen during each of the age groups and how important it is that we have a transition of care and that we're not just graduating these kids out of the NICU without any sort of pulmonary follow-up, both for their own care and also for our learning, as we know we need to learn how to treat these folks and what to anticipate in years down the road. So I think it's, again, really important to highlight we need to focus from the start, from the NICU, how do we get these kids into good pulmonary care moving forward? So just in 2023, the BPD collaborative put out discharge practice guidelines. I'm not gonna do any justice by this one slide alone, but really focusing on what is a good discharge practice from the NICU and how do we get these kids good follow-up where they need to be seen throughout life even if they're seemingly asymptomatic. And really all of these kids should be seen by a pulmonologist at least once if they're mild and certainly followed more regularly by an outpatient pulmonologist in the pediatric world in the first one to two months after discharge from the NICU. Some of the things that we look at in our sort of discharge care coordination is also gonna be really important to set them up for success. I think if you have an area where you have a multidisciplinary clinic, you're gonna serve these kids the best where they can see all of these providers, but really making sure that they know what their care is gonna look like at home, what their child's baseline is like, and that they can use all the equipment properly that they need. Again, I'm not gonna go into a significant amount of detail here, but just knowing that recently over the last decade, we've had a lot of input from the American Academy of Pediatrics, the American Academy of Family Practice, and the American College of Physicians are all sort of working together and have put out a lot of recommendations, 2012, 2018, again in 2023, just recommending that we're really focusing on transferring our patients and putting a whole transition process together into the adult world to limit their complications and increase their adherence to therapies and follow-up care. There's a really nice website, the gottransition.org. I think some of our colleagues are gonna be talking more about this in future talks, too, this week, just sort of preparing our early adolescents throughout the decade of their life that they're gonna be transitioning into adulthood to set them up for success. So with that, I'll thank you guys for listening and I'll pass it on to our next speakers. Thank you. Thank you very much, Dr. Gishu. That was really great information. I am now going to be doing the last talk, which is essentially on prematurity and sleep disorders. And as we were putting together this talk and we were talking about whether this should be included within the talk that Dr. Gishu just gave or whether it should be a separate topic, it turned out that there was so much information that we thought we would make it a separate topic. So that is essentially what I'm gonna be focusing on because this was not necessarily covered in Dr. Gishu's talk. So let me just set a timer for myself so that I don't overstep. So I'm a clinical professor of pediatrics at Stanford and I'm the medical director of our sleep lab. And my predominant interest clinically is in fact the long-term follow-up of children with prematurity and sleep apnea. So what I was thinking about as I was putting together the learning objectives were, I would like the participants who are here to be able to describe the differences between sleep disordered breathing in term and premature neonates because there certainly is a difference. To describe the impact that this sleep disordered breathing has on preterm infants in contrast to term infants. To describe the natural history of what actually happens as these children kind of get older and then be able to hopefully define future research needs for this specific population when it comes to sleep disorders. Overall, the context that I was framing these learning objectives were, should pediatric pulmonologists and adult pulmonologists ask the patients that they are seeing in clinic, were you born preterm? Especially when it comes to sleep disordered breathing. So I hope to answer that question as we go through these few slides that I have. This is the first study that I actually wanted to talk about. This was published in 2003 by Dr. Rosen and Dr. Redline. And this was in fact the first study that actually looked at prevalence and risk factors for sleep disordered breathing in children who were eight to 11 year olds at the time that the study was done. And the other thing that this focused on other than prematurity was race. In fact, it was one of the very first examples within the pediatric pulmonary population of health disparities related not just to prematurity but also to sleep disordered breathing. In essence, what they actually found was that in this cohort of 850 children in which 46% were born less than 36 weeks of gestational age and 17% were actually less than a thousand grams. All of these children were part of a sleep cohort that had actually completed home polygraphy studies. So there was no EEG, but there was oximetry data. There was chest and abdominal movement. And they were able to calculate indices of OSA. Now the criteria that they were using because this study was published in 2003 are not the criteria that are actually followed in our sleep labs today for the diagnosis of hypoptic events because these were measured very differently. Nevertheless, utilizing their criteria, they discovered that sleep disordered breathing was four to six times more likely in black children. And that sleep disordered breathing is three to five times more likely in preterm children as compared to term infants. This is the graph. And these are their definitions of sleep disordered breathing. One definition was obstructive apnea hypopnea index greater than five events per hour. Another definition was obstructive apnea index greater than one event. And then a combination. And when you're looking at the risk factors over here, the risk factors that they actually chose were race and being preterm. And you look at the odds ratio of having developed sleep disordered breathing by any definition that you see over here, you can actually see that the odds ratio are increased when you're black and when you're preterm. So even if you use a varying definition of sleep disordered breathing that is either more inclusive or less inclusive, this data tends to hold true. So one of the things that we think about as pediatric permeate sleep medicine doctors is if you have untreated sleep apnea, what is gonna happen to your brain? So this study looked at the variation of cognition and achievement with sleep disordered breathing in full term and preterm children. And it did definitely detect differences between full term and preterm children. This was the same cohort, but it was five less children. So it was 835 children, 46% of the sample was premature. In this sample, 8.35% had SBD according to study criteria. This is a much higher prevalence than what is generally accepted in pediatrics of obstructive sleep apnea prevalence usually being about two to 4% in most neurotypical children. Snoring history was the thing that they found most strongly correlated with cognition and achievement indices. So they are defining snoring history as habitual snoring. So this is three or more nights per week. An unadjusted analysis showed that children with sleep disordered breathing had poorer scores on all tests with a stronger association in preterm children. So in this particular graph, you can actually see that these are the scales that they had used. This is the unadjusted odds ratios without sleep disordered breathing with sleep disordered breathing and you can see the difference. The P values are all less than 0.001. So this was in fact an association that was very strong and that was maintained on all of these different scales of achievement that they were actually using in these populations. So this means that preterm children are predisposed to having sleep disordered breathing and preterm children are predisposed to greater neurocognitive deficits because of that sleep disordered breathing. Then when you think about a clinical sample, in this retrospective case control study, prematurity was evaluated as a risk factor for sleep disordered breathing in kids less than two years of age. So they selected about 100 kids. They were less than two years. They had all been referred for polysomnography. This sleep study was published relatively recently so they were actually using ASM criteria for the definition of pediatric STD. 31 kids were premature. Many of them are from 24 to 34 weeks of gestational age. Preterm children in this sample also had increased odds of sleep disordered breathing with the criteria being an apnea hypopnea index greater than five. The odds ratio for that increased risk was 4.3. They were also noted to have more hypoxemia, more sleep fragmentation and more central apnea. In these figures that you can kind of see over here, in A and B you have the weight here on the x-axis, the AHI on the x-axis and the weight on the y-axis. In A and B you can kind of see the association and what happens with the apnea hypopnea index and the oxygen desaturation index when the weight is low and the AHI is high. This graph actually shows what is the percentage of kids that have sleep disordered breathing and that is directly related to premature birth. So you have the less than 26 weekers, you have the 26 to 27 weekers, you have the 28 to 31 weekers, the 30 to 36 and then the term. So it means that as you move towards term there is definitely a difference in how apnea hypopnea indices mature and change. You can see that in this graph over here in the same cohort of kids when they had two sleep studies that were a few months apart their AHI fell significantly. This means that this is a disorder that does actually improve with age even in children who are born preterm. So now I presented to you a lot of data that looks at the risk of sleep disordered breathing with preterm birth in early childhood. What actually happens when people get older? In this particular study that was actually the only one that I found that actually has looked at this in a national cohort. This was done in Sweden. It was done in a birth cohort that had 4.1 million adults at the time that they did the study. And so the children who were born in the study and who were enrolled in the study, they started in 1973 then they followed the cohort until 2014, until age 43. They adjusted for perinatal and maternal factors. They also did a co-sibling analysis when there was more than one child in the family to rule out familial factors that could affect their results. They made the diagnosis of sleep disordered breathing by looking at records where there was a diagnosis made by another clinician of someone having sleep apnea or sleep disordered breathing. And in this particular Swedish population they actually found that preterm birth, extremely preterm birth is associated with 1.4 fold and 2.6 fold risk of sleep disordered breathing. This lines up very nicely with the previous data where I showed you where extremely preterm birth has a much higher EHI as compared to term birth. In this particular study, if you were to look at this figure you could kind of see that represented. The red is the one that is extremely preterm, born at 28 weeks with an adjusted sleep disordered breathing right up here at the top. It comes down, then it goes up again later in life. This is age in decades. So 10 years, 20 years, 30 years, 40 years. Then you are looking at very preterm which are 28 to 33 weeks. They follow the same trend. That late preterm which is in blue and then full term which is right here. So this will actually clearly at least represents to me that in this particular Swedish cohort of children who were followed until the fourth decade of life, preterm birth really did affect the severity of the sleep disordered breathing that they underwent. And it did not completely normalize even when they were adults. A similar study was done in Finland where they looked at very low birth weight children and they assessed their increased risk for sleep disordered breathing in young adulthood. This was actually called the Helsinki study of very low birth weight adults. Again, the only paper that I could find that actually looked at this population. Interestingly, as compared to the study previously shown in preterm children, this study also found that in very low birth weight kids, there is an increased risk of sleep disordered breathing in adulthood. Their principal outcome variable, however, was chronic snoring. And they found that chronic snoring is 2.2 times more likely in the cases compared to the control group. The other cofactor that they found was exposure to maternal smoking during gestation as being a significant factor that could affect the later development of sleep disordered breathing. We know as pediatric pulmonologists that maternal smoking is definitely associated with SIDS. It appears that it might be associated with other things that have to do with maturation of the airway. So when we are looking at this from the point of view of we now have data from cohort studies that have clearly established that being born preterm leads to an increased risk of developing sleep disordered breathing and neurocognitive deficits and problems with growth, that those things actually persist until at least the fourth decade of life as best as we can tell based upon European studies. Is there a recognition of this in national guidelines? So as I was trying to do a search for this, I found this document from the National Health Service in the UK. This is the document that they have published as a guideline to their primary GPs or their pediatricians about what to do in follow-up for the preterm children in their practice. So they specifically include sleep problems, including sleep apnea. So this at least is happening in the UK. I was not able to find any other national guideline that included this specific assessment of sleep disordered breathing. Here in the United States, we have a clinical practice guideline, which is the diagnosis and management of childhood obstructive sleep apnea syndrome. This was published first in 2003. It was updated in 2012. It specifically includes infants younger than one year of age. So there is no official recommendation from the AAP about looking at preterm children specifically with the risk of sleep disordered breathing. So in summary, it's very clear, and I hope it's clear to you as well, that preterm children are at high risk for the development of sleep disordered breathing in childhood, in adolescence, and as adults. That untreated sleep disordered breathing in premature children can lead to neurocognitive differences and decrease the necessary weight gain, which we just learned from Dr. Koshue, is so important for lung development. That the optimal treatment for sleep disordered breathing in premature children remains undefined. No one knows whether TNA is actually effective in them. Would the advanced modes of noninvasive ventilation that Dr. Kalra talked about serve them better? TNA is recommended as the curative treatment for OSA, but only in children older than one year of age. And so I do think that both pediatricians and adult primary doctors, when they are seeing patients, should definitely have a question that says, were you born preterm? Especially when it comes to sleep disordered breathing. Thank you.

pediatric healthcare

pediatric bronchiectasis

diagnosis

treatment

positive airway pressure therapy

bronchopulmonary dysplasia

lung function

prematurity

transition care