I'm Maria Castro, I'm an associate professor at the University of Alberta in Canada, and I would like to start saying that my university is located in an Indigenous land, it's name Treaty 6, and it's the Indigenous land of First Nations and Métis. I also want to thank my fellow, Florence Beer, who could not be here today, but she definitely participated in putting this presentation together. Get ready to vote. I only have one question for you, but it's a very important question, and while you do that, I'm going to put my clock, because I want to be accountable for my time. I guess I can just read my lesson objectives while you guys do that. Today we're going to talk about diagnostic options of sleep disorders, breathing, and a few updates that have been in recent guidelines, and hopefully at the end we can discuss current literature on pediatric indications for therapy. So here's my question for you. I have a 9-year-old otherwise healthy female who snores on a regular basis. She's been seen to have apneas and gasping, complains of restless sleep, and she's had learning difficulties over the last year. Familiar? Certainly is for me. Tell me what her pediatrician should do, and please keep in mind the resources available in your area when you answer the question. Wonderful. Thank you very much. I hope I can prove you wrong. So in 2012, I will remember Carol Marcus published Diagnosis and Management Guidelines of Obstructive Sleep Apnea in Childhood, and since then, PSE is still the golden standard for diagnosing OSA in children. But limited to limited accessibility and blah, blah, blah, many other reasons that we all know of, there has been significant advocacy work and society statements asking for additional diagnostic methods. There have been several guidelines published since Carol Marcus published her guidelines in 2012, and I want to go through some of them to give you some updates. So this is the Diagnosis Pathway Algorithm from the recently published British Thoracic Society Guidelines, who is focused on children who are otherwise healthy, have no syndrome comorbidity, have not had her tonsils and adenoids out, and that are above 2 years of age. In those children, the strong clinical suspicion of OSA or home video clips are sufficient to consider surgery and refer the patient to our ENT colleagues. The guidelines also recognize that overnight oximetry and PSQ questionnaires are first-line diagnostic testing for OSA in children. And if you use those, they recommend that you use cutoff of PSQ above .33 or ODI 3% above 7 events per hour to also kindly send those patients to our ENT colleagues with no overnight oximetry. And it's really when there is clinical uncertainty, for instance, patients who are symptomatic but the overnight oximetry is normal, where other testing should be considered. It's also new from this guideline that they recognize that cardiorespiratory sleep testing at home is an option as far as their CO2 monitoring associated with that. The guidelines also warn us to not use just ODI or just AHI to guide clinical management. So remember that no matter what testing you use, do not just use the numbers to decide what the patient should do next. I have to say, I found a few papers supporting this approach in the last few years. I'm not going to go through all of them, but I want to show you a couple of them. So this paper by Van Eden published in the Blue Journal in 2021 used data from almost 600 children below 5 years of age that belong to the CHILD cohort. For the ones not familiar, the CHILD cohort is the largest longitudinal cohort in Canada. What they do, they recruit those patients at birth or even before birth. They run multiple respiratory measures and respiratory sleep behavioral questionnaires through the first five years of life of these children. What this group did is use multi-centered data to come up with an easier diagnosis of sleep disorder breathing. So they use the sleep-related breathing disorder items of the PSQ questionnaire and they came up with a score that they call it SDV-EC score, which makes sense to me. Because all they did is to subtract the age at the first reported snoring from the age at the most recently positive PSQ. And then they use mathematical analysis to come up with risk groups and to predict trajectories. So as you can see here, the green line represents a group of early onset SDV symptoms that resolve the symptoms by three years of age. Another late onset group that had the most of the symptoms between two to five years of age. And then another group that started to have symptoms very early on and persisted by five years of age. For the ones who are wondering where you saw this before, this figure is very, very similar to the childhood asthma phenotypes that Fernando Martinez published in 2004. But not only that, then they use multi-regressive analysis to try to predict who would struggle at five years of age. And they found that this SDV-EC score actually predicted who will have abnormal behavioral scores at five years of age. In this other study, Hornero and his team recruited over 4,000 habitual snoring at two to 18 years of age from 13 pediatric sleep symptoms around the world. And they did that because they wanted to validate a new automatic analysis of overnight asymmetry that estimated AHI. And fair enough, as you can see here, this is the nocturnal polysonography AHI on the left side. On the top, the estimated AHI. And as you know, they correlated pretty well, and they have sensitivities and specificities that were pretty good, especially in the severe group with high AHI index. Not really that different of the ODI-3 percent, though. Since then, there has been three systematic review meta-analyses published in OSA Diagnosis in Children. I'm just going to talk about a couple of them. Wu in 2020 determined that if you really want to stratify OSA diagnosis, you need PSQ-plus oximetry. But, you know, PSQ alone had enough sensitivity to detect most of the moderate to severe cases. Gao in 2021 determined that the sensitivity or specificity of new mathematical methods to interpret overnight oximetry were also pretty good. And there is a recent systematic review revising the evidence of questionnaires and anatomical features and oximetries, but no meta-analysis was done. But what happens with children who actually have comorbidities, they are less than two years of age, or they already have an adenotoxielectomy? On those children, the BDS new guidelines recommend to use either cardiorespiratory sleep testing or PSG, whatever is available in your center as far as there is some kind of CO2 monitoring. They also warn us that AHA or ODI is not really validated for these children, and therefore the clinical decisions need to be done in clinical context and have symptoms as the guide, which is not really different than guidelines from 2012. I did find one paper that tried to challenge that approach. The paper from Truco 2020, what they did, they tried to use the McGill score to determine sleep disorder between children with a bunch of different comorbidities, and they basically failed. They indicated that abnormal McGill score was insufficient to diagnose SDB in children with comorbidities, and the reason for that is because the positive predictive value was actually very poor. So BDS guidelines refer to new ASM manual guidelines stating that further treatment should be considered in patients who have AHI above 5 or CO2 levels above 50 mmHg or at least 25% plus some kind of feature of airway obstruction. This approach might be fine for children with poor airway obstruction or with obesity, but colleagues in the room who deal with neuromuscular patients might not be as happy as I was. Thankfully, CHESS published neuromuscular guidelines in 2023, and they have a very clinical approach to management of these patients. On the left side you can see the whole algorithm of follow-up of this patient. On the right side are the criteria to initiate NIV, and basically in summary, when there is abnormal lung function and the patient is symptomatic, it's enough reason to initiate NIV, as well as if the patient has an overnight oximetry with time under 90% for more than 2% of the sleep time or abnormal capillary awake gases. It also recognizes that when the lung function is abnormal, no symptoms are necessary, which I find fascinating because most of my neuromuscular patients, they're always fine. They never tire. They never have fatigue. So I'm actually glad that there is a criteria that doesn't require the patient to complain. That leaves us with needing PSZ only when there is some kind of disparity between the clinical symptoms and the diagnostic testing. So not all of the patients will need a PSZ to initiate therapy. And when that's the case, the new guidelines recommend to follow ERS guidelines to initiate PAP therapy, which include AHI above 5 events per hour, transcutaneous above 50 for more than 2%, not 25% of the sleep time, oxygen saturation below 90% for 2% of the sleep time, and other few parameters. I have to say, I could not find really evidence or data that support this PSZ criteria. They do make sense and come from expert opinion. And maybe we need to do a little bit more work into backing up those criteria. Last slide. There are a few diagnostic testing coming up. So we might have to put this session again next year. So drug-induced sleep endoscopy is used by ENT to determine the level of obstruction. It might facilitate to target interventions, but it's still not diagnostic. And then there are cooler studies coming up with MRI imaging, doing dynamic airway assessment, genetic testing, videotaping scores that are being piloted to use scoring to diagnose OSA and others. There is also an arising literature on different metabolic markers that evidence the association between OSA and metabolic disease that they're not diagnostic, but they reinforce the need for PAP, and they might be helpful in to assess the effectiveness of the PAP therapy. So open your eyes for new literature because it's coming. I would also say that my group has submitted a paper to Sleep Medicine with the meta-analysis of some of those biomarkers. I checked this morning, it hasn't been rejected yet. So hopefully we have the papers. My key points for today, questionnaires and overnight oximetry seem sufficient to diagnose OSA in uncomplicated habitual snores prior to adenotoxin electomy. Right now, if there are comorbidities, patients are less than two years of age, or there hasn't had an adenotoxin electomy, further testing might be necessary. It is less clear when to initiate PAP therapy for these patients. Symptomatology is still a guiding principle, but there is more evidence supporting that. If you have symptoms and there is any kind of objective diagnostic testing, that includes CO2 monitoring, PAP therapy might be required. In children with neuromuscular diseases, it's not different except that PFT or empergassis chains are sufficient evidence to initiate NIV, and PST is only necessary if there is uncertainty. And last point is that there is an arising body of literature on metabolic markers that might be useful in monitoring PAP effectiveness. That's kind of all I have to share with you. So I'll now talk about treatment of persistent obstructive sleep apnea in children. And the title was about in the era of personalized medicine. But maybe I'll disappoint you a little bit in this aspect. So I work at Children's Hospital of Eastern Ontario, Ottawa, Canada. And these are my objectives, and I will go right into them. So the current treatment approach to children with obstructive sleep apnea really include, as a first step, adenotoxin electomy in otherwise healthy children, but also children with obesity or underlying complexity, complex diseases such as Down syndrome, in the context of presence of adenotoxin hypertrophy. Sometimes you could trial anti-inflammatory treatment, including nasal steroids and or leukotriene antagonists, as there is some biological plausibility that they may be helpful. And also orthodontic treatment, if there is moderate obstructive sleep apnea and an indication for orthodontic treatment. Weight loss should always be a treatment approach in children with obstructive sleep apnea in the context of obesity. But we know this is difficult to achieve in the short term, and also to maintain. Well, if you have a child, then with obesity, medical complexity, or severe OSA, following adenotoxin electomy, there is a higher risk of persistent obstructive sleep apnea. And then the current treatment approach is prescribing a CPAP that's limited because of low adherence, and this will be discussed by the next speaker. So we did come a long way since this case report of a child with hypoventilation and corporeal malady caused by upper airway obstruction published in Journal of Pediatrics in 1965. Maybe on our way in a journey towards a more personalized approach, even in children, but we are not, unfortunately, there yet. Our adult colleagues have done quite well using mostly invasive techniques, looking at endotypes, so the underlying pathophysiology of obstructive sleep apnea in adults. And there is a wonderful review by the Australian investigators, as you can see here, just summarizing the evidence we have in children so far. So our adult colleagues look at the underlying pathophysiology, and in addition to anatomical treatments, they may use treatments that decrease the arousal threshold, alter the loop gain, or also help neuromuscular tone to improve obstructive sleep apnea, either alone or in combination with anatomical treatments. However, currently, we have some treatment options, and we have the advantages and limitations, and I will base my talk on this personal view that we published with my colleague Indira Narang from SickKids, where we looked at the different treatment options in addition to PAP in children with persistent obstructive sleep apnea following adenotoxin selectomy. So these included pharmacotherapy and PAP treatments, and also non-PAP treatments that are sometimes surgical, sometimes are not. But we also looked at the socioeconomic determinants of health, as these are closely related to persistent obstructive sleep apnea, and take into consideration the availability and accessibility of the treatment options that we discussed, and took into account the shared decision making, which I think sometimes in our busy clinic practice forget. One of the things that I want to mention first is weight, the importance of weight loss management. So this is a meta-analysis looking at weight management strategy with diet and exercise, and they included 10 studies, and 90% reported decrease in obstructive sleep apnea in the context of significant weight loss. Obstructive sleep apnea was normalized in variable percentages, but there were reductions, as you can see here, both in AHI and ODI, and very significantly, 75% of the adolescents reported improved sleep duration, and we know how difficult this is in adolescents. But as I mentioned, it's difficult to maintain, to achieve significant weight loss, and then to maintain it with diet, exercise alone. Sometimes if there is a morbidity, that's metabolic morbidity in patients, including adolescents with obesity, bariatric surgery is considered. And in these two studies, one of them is case serious, you can see that obstructive sleep apnea improves significantly after significant weight loss. So that's important to always consider, especially in the context of comorbidity. So weight loss strategies, whether medical or surgical, is efficacious in treating obstructive sleep apnea associated with obesity in children, and of course, it's also important to improve other health-related outcomes. However, we know it's difficult to achieve and maintain, and it requires high resources to achieve a medical weight loss. Bariatric surgery is also invasive, there are some complications associated with it, and then it's not always available for children in many centers. Now in adults, they talk about changing the face of obstructive sleep apnea with the advent of having new weight loss medications. There's no literature yet about the efficacy of these weight loss medications in children, but this could be something that we'll see in the near future. Next I want to talk about heated high-flow nasal cannula that we use very frequently in our pediatric esthrology practice in the context of bronchitis, pneumonia, and NICU care. So it does generate positive airway pressure that's not very high in the ballpark of around five centimeters of water. Because it's an open interface, we cannot measure the pressure. And because the gas is supplied at a constant flow, we cannot neither monitor or adjust the pressure. So we have to know these limitations. However, it's not just through that pressure that's created with the high-flow nasal cannula, but also the stimulation of the upper airway and improvement in lung volumes, increasing the tattering of the trachea, and also the washout of the nasopharyngeal death space that's supposedly helping upper airway obstruction. There are some studies looking at this in sleep lab, comparing, just studying it in children who were intolerant to CPAP, usually with medical complexity, with or without oxygen to improve oxygenation as well. And there's a recent study from sick kids, again, looking at this in a single randomized trial and comparing high-flow nasal cannula with a CPAP in children with obesity or medical complexity, and showing that that's actually very equivalent in treating obstructive sleep apnea and improving it as well. So it can be beneficial in children with medical complexity, persistent obstructive sleep apnea who are CPAP intolerant. It's limited because the studies are not just one randomized study, they're usually small numbers, single centers. And unfortunately, it's very limited because of the home units that are not offering adherence monitoring and alarms, and very limited in our setting in Canada, that it's not covered by insurance and it's a quite high-cost therapy. Positional obstructive sleep apnea is very popular in the adult world, and it has recently gained more importance in pediatrics as well. It's defined as supine AHI being two times higher than non-spine AHI, and the prevalence of positional obstructive sleep apnea is quite low in children before adenotonslectomy who are otherwise healthy, but high in adolescents with obesity after adenotonslectomy. And this can be treated with a positional device, and there is a pilot study looking, and Dr. Zha is among us who performed the study, and they looked at the use of this device in children with obesity or, again, with medical complexity, and showed that there was improvement in obstructive sleep apnea in these children. So although we have very limited data, I think it's important to pay attention to this because maybe it's not that effective as a monotherapy, but it can be used in combination, for example, to decrease the pressures of PAP and having a better compliance. But I also think it's very important because it can be used in resource-limited settings and may be helpful to decrease the health disparities that we see among children, including children with obstructive sleep apnea. Of course, limited by no long-term data on efficacy, comfort, adherence, and the device cannot measure the objective adherence. So Maria mentioned drug-induced sleep endoscopy. I think this is one of the most valuable, in my opinion, in addition to high-flow nasal cannula. This is a flexible fibro-optic endoscopy performed during a sedated sleep, mimicked sleep. And this is to target, to plan targeted surgery in the airway with identification of sites of obstruction. And here you see the sites of obstruction that the ENT surgeons look, mostly anti-surgeons, some pediatric respirologists as well. This study looked at 139 children from Belgium, and they did post-somnography DICE and planned their treatment based on the DICE. So they found that lean children had isolated adenotranslator collapse while children with obesity had circumferential collapse. And DICE-directed treatment effectively improved OSA in all children, including obese children. And here you can see on the graph that with the increasing Z-scores of BMI, children were more likely to use CPAP as opposed to adenotranslectomy. So I think this is very helpful, and there are many studies now out there. I just want to mention this one, including 100, which included 150 children. Here you see that DICE-informed surgery in 72% of children who did not, who had persistent obstructive sleep apnea, and only 8.5 children who had no previous adenotranslectomy, which brings me to the use and the limitations. So it could be beneficial, especially in children with medical complexity, and this really includes Down syndrome very much, and persistent obstructive sleep apnea after adenotranslectomy, and laryngomalacia, and this is usually sleep-onset laryngomalacia, so this is not the infantile laryngomalacia that we know, but limited, of course, still with standardization. Even Europe and U.S. use different sedative medications, but our ENT colleagues are really working on this. So one of the more less-used treatment is hypoglossal nerve stimulation. So stimulation of the hypoglossal nerve, which protrudes tongue forward so that the airway is open, and this synchronizes with inspiration, has been proved to be useful in adults. In children, there are studies only in youth with Down syndrome, and that actually proved to be very useful, but there was a very strict inclusion criteria. So children with morbid obesity, with central apnea, circumferential collapse with dice were excluded because it's just not useful in this group of children. But it did reduce apnea-hypopnea index in all children, but did not resolve all obstructive sleep apnea, so there was still residual obstructive sleep apnea, but the quality of life improved, and these are all CPAP-intolerant children, and the adherence was quite high. So there's a recent publication from the Journal of Nursing, Pediatric Nursing, and they did a qualitative study interviewing parents of children who were referred for hypoglossal nerve stimulation. This sentence just struck me. Parents described being desperate at acceptance of standards of care for treatment of obstructive sleep apnea. So I think, really, we need to be mindful of, yes, this is difficult, this is limited, but it's a resource, and we really have to remember how desperate our parents are. So personalization, hypoglossal nerve stimulation reduces AHI, improves symptoms, and quality of life, which is very important in adolescents with Down syndrome, and it can be a potential therapeutic option for difficult-to-treat patients who are not morbidly obese, and we just have to accept those limitations. And because of that, of course, then it's not very generalizable treatment, and also expensive, invasive, and needs special services because it's a surgical procedure. Last, I want to mention about shared decision-making, because I think we heard about not being stuck on numbers from Maria. This study looked at 50 families whose children had obstructive sleep apnea without tonsillar hypertrophy, so similar to persistent obstructive sleep apnea after adenotonsillectomy, and they had a shared decision-making model where they discussed the treatment options with the families or the control group where they had their usual practice. So after their initial visit, agreement between families and providers on the best treatment option was 91.7% in study group, and it was only 46% in the controls. And very importantly, although CPAP adherence was still very low in the patient group, in the study group, it was still much higher than the control group, although this did not reach statistical significance. I'm sorry, so this is the last therapy I want to mention. So this is still very early. This paper just came out, but in adults, there is a strong support of use of otomexetine and oxybutynin for obstructive sleep apnea. Now they're looking at which patients would benefit from it, and there are some similar medications that are now tried as well. So these medications basically decrease the sleep-related hypotonia of the upper airway muscles and increases the tonus of the genioglossal muscles. So this was trialed in 11 children with Down syndrome and was successful in decreasing the number of obstructive apnea hypopnea index, and this paper actually just came out. And the most common adverse effects were mostly mild, and they were in the higher dose of the medications. So they didn't have a control group, they just had low and high dose, and both doses were equally effective. So this can also be an option in the future. So before I go to my conclusion slide, I just want you to consider that you don't have to go to the PAP therapy immediately. There is a DICE that you can think about in parallel, or if there's a CPAP failure after so many months, we just suggested three to six months, then you can still consider DICE. And if there is a failure of DICE, or you can't use a PAP, then consider other treatments that we just talked about. And we always have to advocate our patients. We do have some patients on hyponasal cannula, although it's very difficult to get funded in Canada. So I'd like to just close saying that obstructive sleep apnea is a heterogeneous disorder, and a one-size-fits-all approach is no longer valid, and it shouldn't be. Although current treatment options for persistent obstructive sleep apnea in children are limited with low efficacy and adherence. Maybe Rakesh will tell us how to improve that. Many new therapeutic strategies are in the pipeline, and I didn't talk about some of those, and I'm happy to discuss afterwards. And I just want to remind you, patient preferences and shared decision-making with families and children for therapy should be just part of any personalized medicine. Thank you for your attention. Good afternoon, I'm Rakesh Bhattacharjee. I'm from University of California, San Diego, Rady Children's Hospital. I've been tasked to describe how to improve PAP adherence, although Rafiqa is now telling us that maybe we shouldn't be thinking about PAP, and I'm gonna maybe suggest otherwise. So I have a few disclosures, but nothing related to what I'm speaking about today. So first I want to start with how we define adherence. So definition of adherence is really based on adult PAP users. This is CMS, Medicare criteria, that they need to wear your PAP device for four hours or more for 70% of nights over a 30-day period, typically in the first 90 nights. It's very specific. But this is what we've been using here in the United States with regards to making decisions about continuing or withdrawing PAP therapy. Well, guess what? There is really no definition in pediatrics, and I actually am thankful that there is no definition because it would make me concerned that a lot of kids would get their devices taken away. That being said, some DME companies will try to force the adult definition, and there's a lot of heterogeneity that you'll observe across the US and other countries in terms of what people define as adherence. Now the one thing to take from this slide is that when you think about four hours of usage in an adult, that's only a sub-small fraction of sleep in a child. The child sleeps more typically about eight hours, and so you would consider that perhaps we should set higher thresholds, but obviously we're reluctant to set higher thresholds because that would make it more difficult to define someone as adherent. Now most of the studies looking at adherence in children has really been sort of case series descriptions, anecdotally, anecdotal information, and I present this slide from Carol Marcus who was really the champion of this concern with regards to how to improve adherence in children. And you can see that there are both positive and negative risk factors that were postulated in this review article, but there's probably factors such as the education level of the mother or the parent, the interactions of the mother and the father and the child, the amount of support that the family has, the amount of education that's being given to them, and then of course the aspect of incorporation of behavioral modification. But this is sort of anecdotal evidence, and I think we're at the stage of where we need to be a little bit more systematic. And I invite the audience to look at this scoping review that was published a couple of years ago where they had the daunting effort of really siphoning through the literature to identify 46 studies that met inclusion. So that gave them 3,208 participants of PAP for children. Most of these studies were from the US, but I thought it was a pretty good representation globally. And looking at how they defined adherence, which was heterogeneous, that the actual figure was 39%. So it wasn't phenomenal, but it's not trivial. And one thing that they tried to siphon through was from all these papers, what was most consistent with regards to predicting adherence? So this is sort of a next step to what we know from anecdotal evidence. And you can see that there's really only two that was consistent. One was sex, and the other was the presence of developmental delay. There were a lot of factors, demographic factors, that were somewhat inconsistent from studies that have less than 1,000 patients, but it did seem that there might be a component of ethnicity, of race. Just the session earlier this afternoon actually highlights that in the adult world, it definitely seems to be discrepancies amongst people of African-American and Hispanic ethnicity. So clearly, this is probably something that might exist in the pediatric world, but it's just not studied with a high enough population. Now, a lot of the data from those studies were kind of various definitions of adherence. They weren't necessarily using what we're now accustomed to, which are these device downloads, which we can actually get objective information, not only of how many hours they're wearing it, but how many nights they're wearing it for, what their mean usage is. And so it's, in my opinion, if you think about our endocrinology colleagues, which they're using glucose monitoring, this is really the equivalence of what we're doing in sleep medicine. To some extent, really, if you have a patient that is using a new device, this is something that should be reviewed every visit, in between visits even. But the thing that makes us a little bit cautious is that there are different algorithms. There are newer devices, related to the recall, that we have newer companies that are reporting data. And we haven't, as a community, been as involved in actually defining what is appropriate for kids. And some of these algorithms were all based on the way adults sleep. And so you have to be cognizant that we are sort of piggybacking off a science that was really developed for adult patients with sleep apnea. And perhaps I would invite the audience to take that next step to be more proactive in using these modalities more specific to kids. Now I think the one thing that's quite critical, though, is that we have this. And so if we have this, we can actually troubleshoot a lot, based on the evidence that's being reported. And this is reported on a nightly basis. So you can see in real time what's going on. And in my opinion, this is sort of the idea of personalized medicine is, I hate to say it to our trainees, but we have this ability to spy on patients because this data is being remotely monitored. And so that gave me the opportunity to actually look at this through a pediatric lens. And we published this a couple years ago where we had access to children that were using ResMed devices through AirView, which is a cloud-based download monitoring. And we could be a bit systematic with looking at what the actual real-time data is. And to my knowledge, this is the largest collection of patients on pap therapy where we could address adherence. And so our age group was over four, under 18, from the time period of 2014 to 2018. And we looked at the first 90 days of usage. And in total, we had just under 21,000 patients. One thing that was most interesting was, which when we're looking at sleep apnea, and I completely agree with Rafiqa, this idea that one size does not fit all. If you look at positive area pressure therapy in the real world, this is predominantly an adolescent treatment algorithm. We're shying away from this for many factors. But if you think about adolescents who are being seen and treated for sleep apnea, in some ways you could actually argue that they are following algorithms very similar to how adults are treated with sleep apnea. And by and far, you can see that the largest age group in our cohort were those children that were over 13 years of age. Now, I want you to remember that because the data is kind of disheartening about that age group. Now, what we found in terms of overall CMS compliance was not too different from that scoping review, was achieved by about 46.3%. And if you look at the idea of how much usage per session, so kids when they were wearing it was about 5.4 hours. And if you think about the four hour rule, this is sort of indicative that kids are sleeping more. And so you would think that the goal should be more than four hours. And then average daily usage, that incorporates the nights that they're not using it, that amounted to about 3.6 hours. Now, if you look at stratifying by age group, this is where I am actually most concerned. So actually the age group that was best was the age group between six and 12. But the adolescents, particularly the ones who are 15 or 18, did the poorest. And that's the age group that are using these devices the most. Now, is this a problem with pap therapy or is this a problem with adolescents? And I don't know that answer because we didn't compare it to other therapies that adolescents had. But as many of you know, adolescents notoriously are not compliant with a lot of their even medications. So this is the population with the highest usage that has the most difficult compliance. And I'm also concerned because unlike these young kids who could potentially outgrow their sleep apnea, these are the children that have sleep apnea perhaps for the rest of their life. Perhaps weight loss will be a big game changer maybe with some of these medications. But I worry that a lot of these kids when they're diagnosed at this age are gonna still have sleep apnea well into adulthood. So we wanted to look at that data systematically and again, we were looking at those that met CMS criteria and these were the risk factors that we were most interested in. And to keep this short, I wanna just present the actual multivariate Cox proportional hazard model where we put all of these variables into one model to see what predicted adherence. And so this is it. And as you can see, as I already mentioned, having an age over 15, less than 18, you're more likely to terminate therapy. If you were a patient using a patient engagement program, you are less likely to terminate therapy. If you had a high residual AHI, you were more likely to terminate therapy. If you had high mask leak and if you had low pressures, you were more likely to have your therapy terminated. So now this is not, this study was not looking at how we can improve adherence, this is just a study looking at what was associated with adherence. And I think, I want everyone to remember that because the next study would be what if we do to adjust these things, could we actually reverse some of this adherence? Now this is a nice study from colleagues in Washington, and I think it's pretty important to think about this idea of cluster analysis because there are different phenotypes of PAP adherence. So in the green here, these are the patients that wear their PAP almost every night and for a high number of hours. But there are patients who wear it, for example, maybe three nights a week for nine hours, and then four nights a week they don't wear it at all. And then there are patients that wear it seven nights a week but for only one hour. And they're gonna have different mean adherence rates, but yet they're, or sure, they're gonna have similar mean adherence rates, but they're very different in terms of what type of a phenotype it is. And perhaps what we need to do better is really identify these clusters and tailor our therapies with regards to that. And we actually recently looked at this in our cohort with children with Down syndrome prior to the Philips recall. And clearly there are patients that don't use their therapy at all and might be now indicated for hypoglossal nerve stimulation. But I just marveled at how many patients actually got the 100% mark with regards to adherence. And these are Down syndrome patients. So yes, there are gonna be patients that PAP is not ideal, but there are patients that are there that you can actually safely and happily, I would say, administer PAP therapy. And so lastly, I just wanna talk about just desensitization therapy. This, again, the reminders, when we think about PAP adherence is that it is multifactorial, that there are many different approaches, and that monitoring is crucial. There's a nice study from Gillian Nixon which showed that if you monitored in the first week of treatment, you can actually identify those patients that are going to be adherent three months later. So there's important things to get from downloads, but I wanna just lastly kind of talk about something that I think needs even further study, and that is the administration of behavioral therapy. Broadly, if you think about adherence to any therapy, education is insufficient, that adding a behavioral component actually optimizes adherence. So thinking about the child in a way to try to engage them to be rewarded in some manner, to be adherent to therapy actually goes a long way. And behavioral therapy is not just rewards. I mean, there's other things that we've learned from adults, motivational interviewing, desensitization, all of these have been well-studied in adults, just not really well-studied in kids. Carol Marcus, who, again, was a champion for us in many ways with regards to delivering PAP therapy, did actually look at behavioral therapy and offered a six-session program and actually found that, on average, children receiving behavioral therapy achieved compliance within three rehearsal sessions. Now, not everybody has a behavioral therapist. I mean, one thing, as Maria talked about, there's not enough sleep labs. Well, there's not enough behavioral sleep psychologists to administer such therapy. And again, this is another challenge when it comes to positive airway pressure therapy adherence. But I just wanna just show this final slide, and that's just basically the notion that if you think that somebody is going to start PAP therapy, that your first role is to really educate them, teach them, identify the phenotype, and then initiate PAP therapy. And then once you initiate PAP therapy, really follow up with them in the very beginning because if they're struggling at the gate, that's when you need to identify them for behavioral therapy and just go all in and recognize that there are pitfalls, but you wanna really throw the kitchen sink at this population because you can actually potentially reverse them, okay? So to conclude, I think PAP adherence in children is quite variable, as I showed from our data, that there are certainly factors that positively and negatively influence PAP adherence, that regular monitoring of this download can help troubleshoot and potentially optimize adherence. Data from our study actually suggested that engagement apps, like MyAir, would actually be supportive. And I firmly believe that if we can be more scientific about offering behavioral therapy, that perhaps that would be the route to improve adherence therapy. Thank you very much. And my name is Iris Perez. I'm a pediatric pulmonologist and sleep medicine specialist at Children's Hospital Los Angeles. And in this session, I am going to focus, in the last 10 minutes of this session, I'm going to focus on congenital central hypoventilation syndrome and discuss the different phenotypes that can actually impact our decisions about treatment options, as well as management plans. So get ready with your phones. Okay. We have a question, just to wake you up. So a four-week-old born at 38 weeks gestation was intubated at birth for apneas and cyanosis. Patient was transitioned to non-invasive positive pressure ventilation, but had difficulty weaning off respiratory support. Could breathe spontaneously, off respiratory support briefly while awake, but upon falling asleep, he's noted to have shallow breathing with CO2 rising from a baseline of 50 millimeters mercury to 85 millimeters mercury with significant hypoxemia. It's good? Yeah, go for it. Okay. Okay, I'm told to go for it. So the correct answer is A, FOX2B sequencing test. Before getting to the presentation, I first would like to give a brief review of congenital central hypoventilation syndrome, or CCHS. So CCHS is a rare genetic disorder of automatic control of breathing and autonomic nervous system dysfunction. It's affected individuals will have hypoventilation and or hypoxemia during sleep, particularly during non-REN sleep, but this can also persist into wakefulness. It is due to a mutation of the FOX2B gene. Most of patients will carry the mutation, which is the polyalanine repeat expansion mutation. About 10% will have the non-polyalanine repeat mutations, which includes missense, nonsense, or frameshift mutation, and about 1% will have the exon or FOX2B whole gene deletion. So CCHS typically presents in the newborn period, and it presents as recurrent apneas, cyanosis. The infant will have marked hypoventilation and hypoxemia without increase in minute ventilation. So they will have hypercapnia and hypoxemia that's quite significant as seen in our vignette, but would not necessarily show the overt signs of respiratory distress. So there would not be a tachypnea or increased work of breathing. And often, these infants will require assisted ventilation and will have very difficult time in getting off their assisted ventilatory support. So to establish the diagnosis, a FOX2B gene mutation analysis is needed. And there are separate tests, and it can be done in sequential fashion. The FOX2B screening test, or the targeted, or the fragment analysis, identifies all known polyalanine repeat mutations ranging from 2024 to 2033. Also, the frame shift and PARMS, as well as the somatic metastasism. And the FOX2B gene sequencing test, or the Sanger test, identifies all known polyalanine repeats and non-polyalanine repeats, and therefore, this is the correct answer in our vignette. And the multiplex ligation-dependent probe amplification identifies copy number variation, and this is the one that identifies the less than 1% of patients who carry the whole FOX2B or exome deletion. What is important to remember is that we have to know when we order this FOX2B gene testing what tests we're really doing. Because sometimes, because, not sometimes, then the current NGS-based assays do not detect the PARMS, and as we all know, this is the most common disease-causing FOX2B variant. So you will not be able to identify the majority of patients carrying the PARMS. Okay, so let's move to our next question. The Sanger gene sequencing test shows FOX2B 2025, confirming the diagnosis of CCHS. Infant is six weeks old, is intubated, and has feeding dysfunction. What is the recommended chronic respiratory support in this age group? A, positive pressure ventilation via tracheostomy, B, non-invasive positive pressure ventilation by mask, C, continuous positive airway pressure, and D, diaphragm pacing. So the correct answer is, you're correct. Majority of you answered it correctly. The positive pressure ventilation via tracheostomy. So the American Thoracic Society in 2010 still recommends that infants and young children be ventilated by positive pressure ventilation by tracheostomy because this is considered to be the most secure type of ventilation, provides the more stable ventilatory support as for a good outcome for these infants. And we're often asked, how about diaphragm pacing? So diaphragm pacing is considered in the toddler age group and this should be considered in those who are full-time ventilator dependent so that if they get ventilated by diaphragm pacing while during the day and still connected to their home vent at night, then that allows mobility and they're not tethered to their home vent. Older children who are stable and only require ventilator support during sleep can be ventilated by non-invasive positive pressure ventilation or by diaphragm pacing. Diaphragm pacing is very attractive in this age group because it allows them to possibly be decannulated. But whatever type of ventilatory support you provide for these patients, it's important to maintain the oxygen saturation about 95% and the CO2 between 35 to 45 millimeters mercury. So when non-invasive positive pressure ventilation is provided, we do recommend that they are placed on time mode or spontaneous time mode with appropriate backup rate and the inspiratory time to reach the goals of ventilatory support. CPAP or bilevel passive airway pressure in the spontaneous mode is not recommended because there is variability in breathing patterns and may not provide the effective ventilation, particularly in those with a lot of central apneas, the CPAP and the bilevel mode in the spontaneous mode will not be effective. But non-invasive passive pressure ventilation, although good for older children, may not be the best in younger children because for several reasons, it poses a lot of challenges. One is that the airway's not secure. There's a potential ineffective ventilation due to leakage, upper airway obstruction, or asynchrony. As you all know, there's limited interfaces in this age group and therefore patients may be predisposed to discomfort, pressure sores, pain, non-cooperation, self-disconnection, as well as low adherence. And because most of the time in this young age group, the NPPV is provided with an oronasal mask, they're at risk for aspiration. And lastly, if you're starting non-invasive passive pressure ventilation at a very, very young age, then there's the risk of skeletal malformation of the face because of the pressure of the mask on a growing face. But do all infants need, or all patients need to be placed on passive pressure ventilation? That is a question that was answered by the group in Seattle and subsequent publications. The buyers at ALF looked at three cases and reported three cases where the patients had Hirschsprung's disease but not, but had very minimal respiratory manifestations. Case one presented with oxygen desaturations up to 60%, but, and obstructive sleep apnea that was attributed at that time to laryngomalacia. So the patient was placed on supplemental oxygen and this did not worsen hypoventilation in this case. Case two is the mother of the case one, and this mother is a college graduate, was asymptomatic even with exposure to anesthesia. A polysomnogram was reported to be normal. And case three at that time had a non-invasive passive, was initially placed on non-invasive passive pressure ventilation associated with an upper respiratory illness and was weaned subsequently to supplemental oxygen. However, at six months of age, this case, this child developed obstructive sleep apnea, central sleep apnea with hypoxemia and hypoventilation. And at the time, the tracheostomy and home mechanical ventilation was discussed. However, the parents opted for non-invasive passive pressure ventilation and was doing well. Few more. And subsequently, Kassi et al reported two cases of also of two patients who had, who were not treated with tracheostomy and home vent but were treated with oxygen therapy. In this case series, case five had apneas presenting us what we used to call alte at seven weeks of age. The polysomnogram showed obstructive sleep apnea and they did well with supplemental oxygen therapy. Case eight presented with hypoxemia and mild obstructive sleep apnea and also treated with supplemental oxygen. However, with case eight, eventually, the patient was noted to have mild hypoventilation on follow-up polysomnography and was treated, was initiated on non-invasive passive pressure ventilation but did not tolerate it, so was maintained on supplemental oxygen. More recently, we described a family who carried the FOX-2B gene deletion and they did not present with hypoventilation. The index case had Hirschsprung's disease, ganglioneuroblastoma, and presented with apnea and cyanosis at three weeks of age. At that time, however, at one year of age, had a FOX-2B gene mutation analysis and at that time, only the polyalanine repeat mutations was looked at and it was found to be negative. But at later years, when more comprehensive testing became available, the index case was noted to have the FOX-2B gene deletion. The sleep studies showed obstructive sleep apnea, hypoxemia, and this patient was obese. And then because of the family testing, the mother as well as the sibling was also found to have carried the same variant. Of note, this family, the sibling as well as the mother and this patient had obstructive sleep apnea and the sibling and the mother were on treatment for CPAP therapy for obstructive sleep apnea attributed to obesity. So why do these patients with CCHS have obstructive sleep apnea? And well, in 2021, the Madani et al looked at the newborn mouse model of CCHS and they found that their mouse model also showed obstructive sleep apnea and mixed apneas and they attributed this to hypoglossal dysgenesis. So why is it important? What is the importance of knowing that these patients have OSA? So we looked at this, like why? Why is it important? What does OSA mean for these patients? So we looked at three patients whose main sleep studies were concerning for obstructive sleep apnea and we did find case one was the initial, was the patient who was described by Kassi et al and what we did find was looking at all the sleep studies this patient really had obstructive sleep apnea improved at some point with adenotonsillectomy and then it was only at five years of age that the obstructive sleep apnea was determined. So this patient would have been missed but it was only at two years of age that the FOX2B gene mutation analysis was done and was confirmed to have CCHS. Case two was the sibling of the initial patient with the FOX2B gene deletion who was for a long period of time was managed for OSA associated with obesity and was treated with CPAP therapy. Again, this would have been missed if not from family testing and then the third case actually was a born prematurely and this initial sleep study showed obstructive sleep apnea, some central sleep apnea and hypoxemia and this would not have been thought of but the infant at that time had an aunt who had the diagnosis of CCHS with nonpolyalanine repeat mutation. So this test was done because of the aunt at the insistence actually of family because the mother was asymptomatic so you would not think that this child would have CCHS. So what is the importance of these cases that I'm presenting? Obstructive sleep apnea can be a presentation. It could actually delay identification of these patients. So when you have a conglomeration of autonomic nervous system dysfunction or you have obstructive sleep apnea that doesn't seem to follow the usual, without the known risk factors, it may be a good time to start thinking of CCHS. So the other clinical importance is that we, as mentioned earlier, diaphragm pacing without tracheostomy is a very, very attractive mode of ventilatory support for older children but in those who have known OSA, we may have to think twice. Maybe they will not do well to being decannulated with diaphragm pacing. As well as those who are treated with noninvasive passive pressure ventilation, it's possible that they would really need higher pressures that would lead them to intolerance and decreased adherence to the invasive passive pressure ventilation. So to sum it all up, what are the CCHS? There are variable phenotypes suggesting an individualized and personalized approach. I was going to say not one size fits all but Rafiq already said that. Hypoventilation may not be the initial presentation and therefore in these patients it's important to continue with surveillance, polysomnography but it's important to have CO2 monitoring to assess the development of hypoventilation. Obstructive sleep apnea may be the initial presentation, may actually obscure the diagnosis of CCHS and may delay identification of these patients. And it's important because CCHS is an autosomal dominant, has an autosomal dominant pattern of inheritance, it's important to pursue comprehensive genetic testing not only on the patient but also on family members. And thank you so much for staying and don't forget to evaluate this session. Thank you.

CCHS

genetic disorder

automatic control of breathing

FOX2B gene mutation

positive pressure ventilation

tracheostomy

oxygen saturation monitoring

CO2 levels monitoring

obstructive sleep apnea

genetic testing