So I would like to thank Sarah and the organization for giving me this opportunity to kind of talk about the respiratory illnesses in children with cerebral palsy. And I think being a pediatrician, I have seen my MedPeds fellows when they transition, is how much of importance this topic is for them in their clinical practice. The objectives of this talk is basically to identify individuals with cerebral palsy who are at high risk for developing respiratory illnesses. Also the management of common respiratory problems in individuals with cerebral palsy and other neurodevelopmental disabilities. Also to review a little bit about the sleep problems in individuals with sleep CP. I promise that slide will be only one. Coming to the background a little bit, just to kind of go through what we what we see and what we are going to see in the adult world. So the commonest cause for mortality and morbidity in individuals with cerebral palsy is respiratory illness. Early mortality is also seen in individuals with cerebral palsy and neurodevelopmental disabilities. Compared to the general population, adults with cerebral palsy have a 14-fold risk of death compared to individuals with no cerebral palsy. Although individuals with cerebral palsy live longer today, and that's probably because of increased availability of health resources, and also with the various screening routines that have come across over the last decade. However, as of now, the commonest cause for death is still still remains to be respiratory illness all the way from 1970. So what the respiratory illnesses for the scope of talk is mostly with relation to acute illnesses like pneumonias, acute and chronic atelectasis, acute and chronic respiratory failure, chronic lung disease, and restrictive lung disease. So the American Academy of Cerebral Palsy and Developmental Medicine came up with certain care pathways, and these care pathways are still in development. However, the latest one that they published was in 2021, and they have basically come up come about about a few risk factors that we need to watch out for in individuals with cerebral palsy in children and adults. The commonest risk factor what they found was the motor function, and they used a classification called gross motor function classification system. So grade five is considered severe, so basically severe motor deficit. Individuals with this are at a higher risk for respiratory illness. In addition, they found that the other most common risk factors is oropharyngeal dysphagia, gastroesophageal reflux, drooling, scoliosis, and malnutrition. This is basically a pictorial representation of all the factors that contribute to the development of respiratory illnesses in individuals with cerebral palsy, more in children than adults. The way this diagram is, it's kind of a little confusing, but I just want you to focus on the top most, the top boxes are all for your motor part of the contribution to the respiratory illness. The one on the right and the left are secondary to malnutrition and GI factors. The GI factors include your reflux, aspiration, and decreased gastric motility. With regards to malnutrition, it's poor general health, and malnutrition is a cause for muscle weakness, which further contributes to respiratory illness. These children and adults also have other comorbidities, like asthma, seizures, epilepsy. All these also put them at a risk for developing respiratory illnesses, especially in the setting of acute seizures or poorly controlled seizures and medications. This is kind of a representation of the pathophysiology of respiratory muscle weakness and its contribution to respiratory illness. So you have two components. One is the respiratory pump problem, and the other component is your parenchymal problem. So you have both of them interwining to produce your basic full pathophysiology of respiratory illness in children with cerebral palsy because of neuromuscular weakness. So they have low muscle tone, hypotonia. They have both weakness of inspiratory and expiratory muscles. They also have some central drive mechanism problems, which all contribute to your respiratory pump problems. With regards to your parenchymal problems, it's mostly secondary due to aspiration and microatelectasis, and over time leading to decrease in tidal volume, restrictive lung disease. All that contribute to a parenchymal problem. The one biggest risk factor that people have talked about in this care pathway and various systemic reviews is oropharyngeal dysphagia, and oropharyngeal dysphagia is generally silent in this population. So all the more reason for us to keep our high alerts for symptoms of these, of this risk factor in children with cerebral palsy. They usually manifest with recurrent respiratory illnesses, so it's important for us to understand that there could be underlying oropharyngeal dysphagia that is contributing to this recurrent illnesses. It's usually investigated by video fluoroscopy swallow studies or by endoscopy. There are certain modes that we can manage this with, and mostly conservative involved in food modifications like thickening of feeds and also using G and J tube feeding. If none of these work, then you have to always think about no oral feeds and just G and J tube feedings as total nutrition for this child. However, we do as pediatricians want children to take part with small tastes just to keep their purposeful movements of swallowing intact and also to prevent posterior drooling. Drooling is a common symptom, I would say, in children with cerebral palsy, and you can also see this in adults with cerebral palsy, and that's usually secondary due to lack of tone basically in the head, neck, and swallowing mechanisms. Posterior drooling is harder to evaluate compared to anterior drooling, and this increased salivation is what they usually refer to drooling. However, in children with cerebral palsy, it's not the increased production of saliva, it's actually a swallowing problem rather than production problem. They have poor swallowing mechanisms, and therefore they have increased oral secretions, and that's what we see as a clinical symptom is drooling. The management of drooling is you have your conservative approach, which basically consists of frequent suctioning, positioning, behavioral interventions. However, these seldom work very well with our cerebral palsies. Most often, we do go to our medications, which is mostly anticholinergic medications. We also use Botox, that is botulism neurotoxin. However, the first step is by using your medications. These medications also have side effects like urinary retention, dryness of secretions, so it's hard to find that good balance by using medications and also your other methods like suctioning and postural drainage. With regards to gastrointestinal reflux and aspiration, they go hand-in-hand. So aspiration can both be anterior grade and retrograde. Anterior grade can be from your salivary secretions and retrograde from your gastric secretions, like gastric contents, and it also can be reflux. They're usually diagnosed by endoscopy and by esophageal pH or with or without impedance, and this is the guidelines from ESPAN in 2017. As I said in the previous slide, the management includes food thickeners, PPI, prokinetics, and baclofen. The surgical management, however, involves gastrostomy, genostomy, fundoplication, and esophageal gastric disconnection. This is on a rare basis, and that is why you need your GI and your surgical colleagues to work with you closely in this population of patients. Airway clearance is very important in these patients because most of them have decreased muscle strength. That's hypotonia and muscular weakness generalized, both including the trunk and the neck and face, and therefore it's important to prevent aspiration. We always have to have adequate airway clearance. So the way you do airway clearance in this population is by chest physiotherapy, and chest physiotherapy can be in form of your high-frequency oscillation or it can be mechanical insufflation and exsufflation. Chest wall mobility also contributes a lot to the respiratory illnesses by in form of, if you have scoliosis, it can lead to altered lung mechanics. It can also lead to diaphragm decreased functioning of the diaphragm. It can lead to decreased lung volumes. So all these contribute towards a decreasing your tidal volume, restrictive lung disease, and also leads to putting you at a risk for respiratory illnesses. These are the two systemic reviews and the care pathways, which was published by the American Academy of Cerebral Palsy and Developmental Medicine. So they came up with this kind of a pathway, and you can see this pathway is kind of, it's got a lot of boxes in there, but I think the way I understand it is it's got four categories. One is you control your risk factors based on what we already talked about, like, you know, you're drooling, airway clearance, atelectasis prevention, you increase gastric motility, you treat reflux. All those factors come in the first column. And the second column is by increasing airway clearance. The third column is where you have chest wall mobility, and I think that is important because it's important for us to know when to refer our patients with scoliosis to our orthopedic colleagues. What is that point where you want to send them, because we as pulmonologists will not be able to determine that. So it's important to see that, and if a particular patient is having recurrent respiratory illnesses and you've kind of taken care of all those factors in your first column, think about chest wall mobility. The other thing that they focused on was your malnutrition, and I think that's of very importance in pediatrics. As pediatricians, we do focus a lot on nutrition, so I don't know how it's in the adult world, but probably my adult colleagues can tell me about it. But as a pediatrician, one of our checkboxes is nutrition. So a little summary on the management. As we already talked about, we need a well-coordinated multidisciplinary team, annual clinical reviews to go through all these risk factors so that we identify certain individuals and treat them for their respiratory illnesses earlier than later. We also want to monitor their nutritional status, gastroesophageal reflux status, and also their ongoing airway clearance regime. Since I also do sleep medicine, I always want everyone to look out for sleep disordered breathing. The CARE pathway, however, did not talk much about sleep disordered breathing. They did suggest that we do a multidisciplinary approach for management of these children, so basically have a multidisciplinary clinic which includes pulmonologists, speech pathologists, dieticians, PT, OT, gastroenterology, respiratory therapists, and social work. Coming to sleep disordered breathing, you have two components. You have the obstructive component and the central component. The commonest risk factors for that is because you have low tone, hypotonia, which can cause pharyngeal laryngeal collapse, causing obstruction. They could also have upper area obstruction because of scoliosis and lung protrusion, prolapse, sorry, poor seizure control because of their underlying comorbidities like epilepsy, and also they need frequent airway evaluations and polysomnograms if they have clinical symptoms suggesting sleep disordered breathing. Some of them also have silent hypoventilation and hypoxemia, so it's good to kind of have a baseline on clinical evals every year on their status of ventilation. The use of non-invasive ventilation and cerebral palsy is your first line of management before we even think about secondary complications or going to a surgical management. The non-invasive ventilation and cerebral palsy is usually by positive pressure for your obstructive sleep apnea. However, in cases of central sleep apnea and chronic respiratory failure, we do use other modes like BIPAP and AVAPs. The challenges for non-invasive ventilation is usually because of the interface. It's difficult to keep an interface because of their dysmorphism and cognitive delay, and also with the possibility of aerophagia and nocturnal feeds. Now, nocturnal feeds is a challenge in this population because we cannot feed them when they're on nocturnal ventilation, so we have to alter their feeds through the day. This is just a brief review of the non-respiratory sleep problems, and the commonest one is insomnia. However, they can have other circadian rhythm disorders too. So in summary, individuals with CP and neurodisability are at higher risk of respiratory illness. Several factors like hypotonia, scoliosis, aspiration, reflux, poor airway clearance, and poor cough lead to chronic respiratory morbidity. Multidisciplinary approach is recommended, and regular clinic evaluation of these risk factors, including the need for non-invasive ventilation. Thank you, and please do not forget to evaluate the session in the app. Hi, I'd like to thank the organizers for having me. I'm Liz Clings from Boston University, and I direct both the Center for Excellence in Sickle Cell Disease and the Pulmonary Hypertension Center. These are my disclosures, mostly about the work I do in sickle cell disease. We're going to talk about sickle cell disease as a chronic dyspnea and chronic vasculopathy, and so my perspective of sickle cell lung disease in the adults is really from the pulmonary vascular perspective, and we're going to talk about dyspnea and how to evaluate it in our patients. I am using the audience response system for one question, and this is the QR code that you can scan, and so I'll give you a couple seconds to do that, but before we can talk about how sickle cell disease affects the cardiopulmonary system, we have to talk about sickle cell disease in itself. As I know from working with many pulmonary and critical care fellows, their knowledge of sickle cell is not so hot. So sickle cell disease is a disease that affects approximately 100,000 patients living in the United States. However, it's a global disease with 250 to 300,000 births occurring each year worldwide, and so big pockets of the population in sub-saharan Africa and India, and why it's important for cardiologists and pulmonologists to know about this disease is that cardiopulmonary complications account for at least 20 to 30 percent of deaths. So this is an autosomally recessively inherited genetic hemoglobinopathy, and so hemoglobin S is a glutamic acid to valine switch in the sixth position of the beta-globin gene, and those who are homozygous for this disease or have hemoglobin S disease have the most severe form, with a median survival in the 50s currently in the United States, but hemoglobin SC disease, a compound heterozygote of hemoglobin S and hemoglobin C, a glutamic acid to lysine switch, it really accounts for about 30% of people living with sickle cell disease here in the United States. Typically this is thought to be a milder form of sickle cell disease, not entirely true. Complications are less common, but they have all of the complications that we have that patients with SS disease occur in SC disease just less frequently. The lifespan is a little bit longer, typically in the 60s and 70s. Sickle cell trait was thought to be normal for many years, not true either, understudied is the better way of looking at it. We're beginning to understand that this may put you at risk for renal disease, thromboembolic disease, and exercise-induced cardiac arrest. Now we're going to switch gears to the heart and lungs, my two favorite organs. And so pulmonary complications, cardiopulmonary complications of this disease affect every single cell type and structure of the heart and lungs. The two complications highlighted in red, acute chest syndrome and pulmonary embolism, are going to be touched upon in this talk. But I'm mostly focusing on the chronic complications, particularly affecting the cardiovascular system, which would be pulmonary hypertension, congestive heart failure, and chronic thrombosis. Before we get into specific complications, I want to talk about how common dyspnea is in the adult population. These are data that were generated at Boston University as part of my K23, where we surveyed 147 adult patients with sickle cell disease and found that 50% of hemoglobin SS adults and 40% of those with hemoglobin SC disease were New York Heart Association class II or higher in terms of dyspnea. And we'll get to how to actually assess for this. But this is a multifactorial dyspnea that's often associated with hypoxemia, particularly with exertion and with sleep in this population. There are both extra pulmonary conditions, including chest wall pain, atelectasis related to this, chronic rib infarct, the chronic anemia, obesity, and particularly in our hemoglobin SC adults, and deconditioning contributing to it, as well as a potpourri of cardiopulmonary diseases. And so you have to keep this in mind when you're evaluating your patients. And the recommendations are really to evaluate all of your adults annually for dyspnea and hypoxemia. And so how do we do this? I will tell you that the question you need to ask your patients is, can you walk five blocks on a flat surface? Or can you walk up one flight of stairs without stopping? 50% of your patients with sickle cell disease will say no to either one of those. And we use six minute walk tests to really objectively test for, first of all, exercise intolerance and hypoxemia with exertion. Oh, shit, I did this again. So once you have a dyspnea patient, this is when you need to proceed to further testing. And so pulmonary function testing, what do we know about it in this population? Well, what we know is from cross-sectional data that was obtained from the Cooperative Study on Sickle Cell Disease, which was a prospective study across 23 centers in the United States, conducted between 1978 and 1998. We analyzed 310 pulmonary function tests and published these data over 17 years ago at this point from adults. And what we found is that in 90% of patients, pulmonary function tests are abnormal in the adults. And that they predominantly have restrictive physiology. This occurs as well as in the pediatric population. But what you see in kids is a little bit higher frequency of obstructive lung disease, and that's because of the existence of asthma in many of our children with sickle cell disease. That seems to peter out a bit as kids become adults. Echocardiography is essential in this population because it's really the main way that we evaluate patients for the presence of pulmonary hypertension. And we know from the work of Mark Gladwin, Roberto Machado and others, that a third of hemoglobin SS adults and between 10 and 28% of hemoglobin SC adults will have an abnormal tricuspid regurgitant jet velocity by echocardiogram. And that was defined as a TR jet velocity of greater than or equal to 2.5 meters per second. That corresponds to an RV systolic pressure of about 36 millimeters of mercury. And why that was important was this was associated with about a 40% 40 month mortality. And the higher your TR jet goes, the more likely you actually have pulmonary hypertension and the worse your risk for death is. And so a PA systolic or an RV systolic pressure of greater than 40, which is what a TR jet of 3.0 is, is associated with about 11 fold odds ratio for death. And so but we know that an elevated TR jet velocity does not mean that you have pulmonary hypertension. There's actually only a 31% positive predictive value and we'll talk about that on the next slide. But that this increases to 62% if you include an elevated NT pro BMP or reduced six minute walk distance of less than 333 meters. Right heart calf is the essential way you make a pulmonary hypertension diagnosis in this population as in every other population. And we know that if you do this, 6 to 10.5% of hemoglobin SS adults will have pH. Whether or not you need to do echoes in everybody in adulthood is controversial. I hope that by the end of my career it will not be controversial anymore because there's so much you can get from echoes in these patients. And so but we're gonna talk about pH in specific. And so what we know about the specificity of echocardiography in this population is based on a meta-analysis done by Omar Nis and others at Cincinnati Children's. Where they looked at 173 adults across four studies where there was both right heart calf and echocardiographic data. And they found that 31% of those patients with an elevated TR jet velocity actually had pH. And when you look hemodynamically at these patients, this is actually what I would call a mild to moderate pH. With mean PA pressures in the low to mid 30s and a pulmonary vascular resistance of about two wood units. Now you need to remember that in sickle cell disease, particularly hemoglobin SS disease, the chronic anemia causes an elevation of cardiac output at baseline. And so we know this from right heart calf data dating back to the 1950s. The baseline cardiac output in these patients is seven to nine liters per minute, so not five liters per minute like what you see in the general population. And so the ATS guidelines, when we led this committee back in the 20 teens, we determined that a PBR of two wood units or 169 to the second per centimeter to the fifth was abnormal in this population. One other thing you need to know about pH in this population, it's heterogeneous disease. And 60% of our patients will have post capillary or pulmonary venous hypertension related predominantly to diastolic dysfunction of the LV. But 40% or so will have pure pre-capillary pH, and we'll talk about that and how it relates to treatment later on. Doesn't matter what you have hemodynamically, pH is a risk factor for death, it's been shown repeatedly in this population. This is a Kaplan-Meier survival curve on the left, from Ellen Mahari when she was at the NIH. And this was using the old definition of pH, of a mean pulmonary artery pressure greater than or equal to 25 millimeters of mercury. And if you had pH, that was associated with a 40% secure mortality. And as is in every other form of pH, the right ventricle is the determinant of who dies. And so this is a study looking at cardiac MRI and a reduced right ventricular ejection fraction. By cardiac MRI, it was also associated with a 60% four-year mortality rate. So where does this pH come from? This is a lifespan disease. And so what do we know about cardiac function in children and adolescents with sickle cell disease? Well, what we know is predominantly obtained from three large studies. The PUSH study, which looked at 510 patients with sickle cell disease between the ages of 3 and 20, and they collected data between 2006 and 2010. They found that about 5% of their hemoglobin SS children and adolescents had an elevated TR jet velocity, which they defined as greater than or equal to 2.7 meters per second. And that when they followed these patients over 22 months, the presence of an elevated TR jet velocity predicted reduced exercise capacity as measured by a six minute walk distance. And then when they followed them longitudinally over a median of 88 months, there were ten patients who died. And having an elevated TR jet velocity was one of the risk factors for mortality. Omar Nis has looked at a lot of imaging in patients with sickle cell disease. And he looked, and others at Cincinnati Children's, looked at 134 patients between the ages of 3 and 22. And really, this is the first time that we started really looking at left ventricular dysfunction in this population. And by cardiac MRI and by echocardiography, what you are seeing is LV dysfunction, predominantly LV fibrosis, leading to diastolic dysfunction of the LV and a left atrial enlargement. The group at Columbia looked retrospectively at 829 echocardiograms obtained from 172 pediatric patients, followed over almost 20 years. And what they found, this is a very strange Kaplan-Meier survival curve, but basically what they found is that as their children and adolescents got older, the frequency of having abnormalities, particularly in their left side of their heart, increased. And so this was the probability of having normal left ventricular function and a normal TR jet velocity. This all decreased over time, and it was most prominent in those who had the greatest degree of hemolysis. Reflected by having hemoglobin SS disease, hemoglobin beta zero thalassemia, and by the degree of anemia. We know that if we think about what's contributing to the etiology of pH in sickle cell disease, it's likely multifactorial. And all of the factors listed on this figure have been implicated in this. My research group has really been focusing on the role of thrombosis in this pathway. And so why think about thrombosis in sickle cell disease? Well, sickle cell patients are hypercoagulable, and they're hypercoagulable for numerous reasons. Some of these are endogenous to sickle cell disease, and this includes the ischemia reperfusion injury and increased inflammation that happens in patients with sickle cell disease. But also there are exogenous factors, the fact that many of our patients require long term intravenous catheter placement. Some of them need hip replacement surgery. Some of them get pregnant and have other conditions that may increase their thrombosis risk. And so when you think about thrombosis within the pulmonary vasculature, it takes many different forms from small vessel or micro vessel in situ thrombosis to large vessel PEs and thromboemboli that can emanate from the lower extremities and the upper extremities, particularly in our patients with indwelling catheters. Some of these may become chronic. And so what do we know about venous thromboembolism in this population? Well, a lot of what we know stems from two large database studies. The cooperative study of sickle cell disease, there was a retrospective review of these data looking at 1,523 patients. And then a large Medicare based patient discharge database from the state of California looking at 6,237 patients. What we've gotten from those two databases is that by the age of 40, 11 to 12% of patients with hemoglobin SS disease will have had a venous thromboembolism. If they had severe disease defined by three or more hospitalizations in the prior year, that risk goes up to 17%. And more concerningly, when the group from UC Davis looked at their California data, in 877 patients with an incident VTE, the one and five year recurrence rate was 13.2 and 24.1%. And VTE has also increased the risk of death by nearly threefold. And this is what led the American Society of Hematology Guidelines in 2019 to recommend lifelong anticoagulation for a first time VTE. Our group has been looking more granularly at what happens to patients after a venous thromboembolism. We look at 402 adults. We have a longitudinal database looking back to 2003. And approximately 19% of our adult population have experienced the VTE with a 49% recurrence rate. And when we look at the five years post VTE, we have found a five to six-fold increase in annualized rates of vaso-occlusive events and acute chest syndrome in the patients with a VTE. And we're looking now, as well as an increased risk, a two-fold increased risk in mortality. We're now looking at our data to try to make the link between venous thromboembolism and echocardiographic evidence of pulmonary hypertension. So in my patients who I have with pH and sickle cell disease, lifelong anticoagulation is one of the treatments that they need. But let's talk about some of the other treatments. And what I've learned about working in this space for almost a quarter of a century, which is depressing, is that you can never forget the sickle cell disease because the sickle cell disease always wins. And so everybody needs to be treated for their sickle cell disease. We currently have four FDA-approved medications for treating this disease. Hydroxyurea, L-glutamine, chrysalizumab, a monoclonal P-selectin antibody, and voxelotor, which is a hemoglobin-modulating molecule. None of these have been directly studied in pulmonary hypertension of sickle cell disease. Hydroxyurea does not actually appear to be protective against pulmonary hypertension in this population from the epidemiologic studies that have been done to date. But it does protect against vaso-occlusive crisis and acute chest syndrome, both of which can promote right heart failure in our pH population. And so because of that and because of the survival benefits of hydroxyurea, we recommend hydroxyurea for everybody. And that was what came out of the American Thoracic Society guidelines published in 2014. There also are some theoretical benefits of the newer therapies in terms of improving anemia and reducing vaso-occlusive events. Chronic exchange transfusion has been studied in a small fashion. This is a case series published by the French group, where patients with right heart cath proven pre-capillary pH were put on a program of exchange transfusion to improve their hemoglobin A concentration over a year. And what they showed was that after a year of this exchange transfusion, there was improvement in symptoms as defined by New York Heart Association class, as well as reduction of PBR. And this is really the science of 13 patients, is really the science that led to the NIH funded sickle cell disease and cardiovascular risk clinical trial that is ongoing now in the United States and Europe of red cell exchange transfusion versus usual care. So do we use PAH or pulmonary arterial hypertension medications to treat pH of sickle cell disease? Well, I'm going to tell you yes, but it's yes in a special subset of the population. To date, we have no placebo controlled randomized clinical trial in this population specifically. However, there are both short and long term case series that suggest benefits. One caveat is the walk fast study of sildenafil versus placebo for patients with an elevated TR jet velocity, not pH. Just an elevated TR jet velocity was stopped early because of increased frequency of vaso-occlusive events and other hospitalizations. And so the question is, well, what to do? So in the patients with post-capillary pH, I do not use PAH therapies because they need to be treated with diuretics like you would treat congestive heart failure. But in my patients with pure pre-capillary pH, I do use them. It's off-label use, but I use endothelial receptor antagonists and I use them in combination with Rio Sagua as my dual therapy of choice. And so I do a lot of a stratification of my patients, but my patients get symptom benefit, exercise tolerance benefit and hemodynamic benefits from these regimens. And so we're going to move into my ARS question, which is coming up on the next slide. So this is a 35 year old female with hemoglobin SS disease and she's diagnosed with an acute pulmonary embolism and right lower extremity DVT or deep venous thrombosis. Other than her sickle cell disease, there were no provoking risk factors. So we're connecting to the live content. Hopefully I don't explode this talk again. And so the question is, which of the following is a correct statement about her long term prognosis? A. She is at increased risk for VTE recurrence. B. Her mortality risk is unchanged. C. She should be treated with short course six to 12 months duration anticoagulation. D. She should not be treated with direct oral anticoagulant. And or E. She is increased risk for arterial thrombosis. We're getting some votes cast. Let this go a little bit longer. Okay, we might be we might be at nine. So So all of you said the right answer, which is great. Those of you answered the question. She is an increased risk for VTE recurrence and so Lifelong anticoagulation is is beneficial. We only have minimal data about what drug of choice but the oral direct oral anticoagulants seem to be better than warfarin in terms of Hemorrhagic risk and risk of recurrence. This is on very little limited data This is actually one of my future directions research-wise We don't know if this puts her to increased risk for arterial thrombosis. And yes, it does put her increased risk for mortality This is my last slide Cardiopulmonary complications are very common causes of morbidity and mortality in sickle-cell disease Likely these problems begin in childhood We need to understand the life the natural history of cardiopulmonary complications in this disease so much better Thrombosis is likely a pulmonary vascular modulator in this disease. We see it in autopsy studies. We see it in our patients and lifetime anticoagulation You know after our first time VTE is essential However, we do not understand if that in any way impacts outcomes This is also in one of my other research interests and there is so much more research need to be done in this population Thank you for listening and don't forget to Evaluate this session in the app and I apologize for me crashing the system Good afternoon everyone and thanks for being here instead of on a sunny beach So we appreciate you being here at this session. I'll try to condense this talk a little bit. So we stay on time I am currently at Methodist at Houston. I am a med peds trained transplant pulmonologist Today these are the objectives that we will cover but we will do this in a case-based fashion and We'll be pretty direct and just talk about each objective quickly Because I want to keep your attention So we have a 42 year old. She has a past medical history of asthma. Her asthma has been worsening She presents to the ED or consulted for admission. This is her fourth ED visit She's had multiple urgent care visits ED visits just in the last three years multiple steroid courses She has a history of poorly controlled asthma Recently placed on Simba court by her PCP about two months ago It's still persistently poor control, even though she has good adherence and good MDI technique She tells you she doesn't really have any past medical history or surgical history She does have a brother with similar symptoms and she's never smoked or vaped. No illicit drug use and So she's a little tachypneic She needs a little bit of oxygen and you get a chest x-ray after hearing some ronchi and this is what you see and So now you're beginning to think to yourself. All right. Well, what are my next steps here? Here's a relatively young adult and I'm seeing a very abnormal x-ray with an abnormal exam. What could this be? Well Are you gonna order more scans more tests? What's your next step and being the astute clinician that you are you decide to take additional history? And so this is where undifferentiated cough wheezing Asthma COPD without a smoking history, especially as outlined by the new gold classification Really lends itself to taking a prenatal neonatal history. And so what does that really entail? Well, if I would argue that at the very least if you encounter a situation like this you ask were you born premature? And if the answer is yes, then you can ask additional questions What was your mother's prenatal history like that? She have any medical problems that you get any prenatal care worth any complications? What kind of mode of delivery did you have to stay in the NICU? Did you receive oxygen were you on a ventilator on BiPAP? Some of your patients will know this and many will not and so She will then tell you yeah I think I know something about being premature and later on she brings you some records and You find out that she had a NICU stay for about two months. She was born six weeks premature She has used MDIs her whole life with little improvement And so that will bring us to our next objective which is defining bronchopulmonary dysplasia. So actually was described first in 1967 By Northway and colleagues initially defined as the use of oxygen for 28 days With corresponding radiographic changes and obviously their subjectivity there And it was thought is actually published in the original manuscript that newborns born with respiratory distress syndrome and bronchopulmonary dysplasia Will recover within three to seven days and have completely normal lungs Well, we've come a long way in on our standing of BPD, but there's still a lot more to understand and so you'll see here the Diagnostic criteria for bronchopulmonary dysplasia and all the pediatricians and neonatologists out there will know this but for my adult colleagues You know thinking about how much oxygen when they needed it Will define bronchopulmonary dysplasia. And so what we're seeing here is that depending on gestational age or post menstrual age and the time point of assessment will define BPD and the amount of oxygen that you're using either at the time of discharge or at 36 post Menstrual age will define the severity and so Mild will be stable and remare at the time of discharge Moderate less than 30% or greater than 30% for severe This remains the most common cause of pulmonary morbidity in preterm neonates and as some of my pediatric Intensivists will say what can we really do about BPD? Well, there's a lot that has been done because now they're over Conservatively speaking a million survivors adult BPD and that's probably underestimated. Let's go back to our case So this lady gets a CT scan because you want to figure out what's going on with her You start her on antibiotics and this is what you're finding. So air trapping cystic changes traction bronchiectasis bronchiolitis and some basilar predominance to our cystic changes And Again for the sake of the time I will move a little quickly and I apologize for that And that really brings us to our next objective which is understanding the pathophysiology of bronchopulmonary dysplasia Now this is something that has been Attempted to be find in animal models. And so what we do know is that this is a multifactorial Pathophysiology and in 2014 the NIH heart Lung and blood Institute workshop proposed that this was multifactorial There's infections inflammation immature lung structure and function hyperoxia mechanical damage due to the mechanical ventilation nutritional deficits all of these lead to abnormal alveolar and vascular changes and looking at it from a Immunological perspective there have been several Pathways proposed by which the mechanical ventilation oxygen toxicity and infections Correspond to these changes So interleukins 1 6 8 and TNF alpha have all been implicated in this process much like we see in ARDS So, what does this lead to altered vascular and alveolar maturity Which will come back to free radical damage and oxidative stress and increased extracellular modeling and in the end This leads to what we're all very familiar with which is impaired growth lung and function and that's the growing theme here but how to make a diagnosis and this will bring us to our next objective is The time course and how old this patient is actually matters, right? there is something called old and new BPD also referred sometimes as type 1 and type 2 and so at the time of surfactant introduction or prior to surfactant introduction as this lady was Born may change What you see and how they are characterized and so in the era of more Or less lung protective mechanical ventilation, although that still continues and prior to surfactant you'll see things like bronchiectasis fibrosis cystic changes and You will see severe restrictive lung disease. You can see patients with spontaneous pneumothoraces and these are of course extreme cases Versus after surfactant use and Lung protective mechanical ventilation. You may see a more nuanced view. These are these patients that may be classified as COPD D Developmental in which they may have a preserved FEV 1 to FEC but an impairment in their spirometry a chronic cough a chronic wheeze And so we'll talk a little bit about that. But the pulmonary vascular changes are what's really really important here So history matters is I hope one of the points that I can come across here as in many other diseases, right? So what you're going to see like emphysema bronchiectasis cystic changes as opposed to maybe some mosaic attenuation or maybe some small amount of emphysema It's going to be a more variable presentation now in our younger adult BPD survivors another way to classify this is dyssynapsis, so this is a Greek word meaning bad fit or Abnormal matching and it's just this idea that when you have prematurity You're going to have the situation where there's a disproportionate size between the airways The size of the lungs and the alveoli and that leads to a lot of that air trapping that we're seeing And so why does this matter and this was defined in the Journal of Physiology? It results in two disease states now what they looked at was adult survivors of bronchopulmonary dysplasia as well as those With prematurity without bronchopulmonary dysplasia, and what they found is that both can have reduced fav1 Both can have air trapping both can have reduced exercise and exercise tolerance and particularly both groups can actually have risk for bifentricular dysfunction and elevated pulmonary artery pressures Particularly with exercise and so this idea of dyssynapsis is what lends itself in addition to the pathways that we saw To this idea of obstruction or maybe of some obstruction with a preserved ratio Exercise capacity was studied in these patients and so oftentimes you're meeting these patients in clinic And you're saying I'm not really seeing radiographic changes your spirometry is relatively normal You have no bronchodilator response or methacholine challenge is normal I don't know why you're short of breath and so doing a c-pet on these folks, and this was bronchopulmonary dysplasia Prematurity and size and age and gender match controls found that these patients tended to have a respiratory limitation Predominantly in their tidal volume important to know Additionally they found that exercise pulmonary artery pressures tended to be higher in this group and That in the in these patients they tended to correlate with the Age meaning how premature they were and how long they were on the ventilator So how to treat them right that's what all of my colleagues want to know they're like great great great Thanks for the history very exciting. I kind of slept through it, but tell me now what to do right so What you would always do for someone with either bronchiectasis or obstructive lung disease Nothing's really changed here Except with understanding that these patients have been sick they require care when it comes to their transition Assess your PFTs do regular monitoring help them understand the world of adult pulmonary care Exercise for or assess for exercise impairment c-pad is reasonable here assessing for pulmonary hypertension in some of these patients particularly those like the ones that you saw with this CT scan is Incredibly important assess their nutrition refer to pulmonary or cardiac rehab Encourage vaccinations assess for mental health Chronically ill young adults need a mental health assessment plain and simple So where did this case conclude and I have to leave a little bit of time for Sarah here? this case fortunately and unfortunately led to transplant so She and her brother were actually both transplanted in quick succession They both had multiple bronchiectasis exacerbations leading to progressive hypoxemia one developed severe pulmonary hypertension and So they were both thankfully Transplanted successfully and are both several months out from their transplant and doing well again. This is a severe case. This is old BPD This is cystic bronchiectasis and these patients needed a new lung to survive much of what we're going to be seeing in clinic Is the opposite phenotype but knowing that there is heterogeneity in the disease? Understanding that there is a Longitudinal reason why these patients have exercise and ventilatory impairment is very important So here are your takeaways and I hope I've hammered them home. It's neonatal and pediatric history, please There's a growing patient population of bronchopulmonary dysplasia. You can see obstructive lung disease You can see prism all of these patients will soon be labeled as probably COPD D in our patient populations Assess for pulmonary hypertension in these patients assess for exercise impairments refer to pulmonary rehab and This takes monitoring care and attention. Thank you all so much for your time All right, thank you so much dr. Botros, I am going to Take it home by Changing the topic a little bit and kind of talking about in general How do we best transition these patients to adult care? So I introduced myself earlier. I do not have any disclosures So we're gonna talk today about challenges associated with transitioning to the adult care. Why is this difficult and how can we do it better? If you all have not yet gotten the QR code, that's back up again for folks and I'd like to ask y'all at what age. Do you think that patients should be transitioned from pediatric to adult pulmonologists? So when they're 18 when they're 21 Some older time never they were children that they should stay with their pediatricians Or is it a life event? They've moved out. They've gotten a job All right So it looks like actually a lot of our audience thinks around age 18 Which I think is is really interesting and kind of as we think about how do patients actually end up transitioning to the adult world? But certainly thinking about it younger is really important So I'm gonna start off with a couple Cases and these are all adapted from real cases that I've seen in the last few years as a pediatric and adult pulmonary fellow There were many many more to choose from you just heard about how common sickle cell is how common Cerebral palsy is and the respiratory manifestations of those how common bronchopulmonary dysplasia is those are only three conditions There are many more there are a lot of these patients out there. So our first patient. This is Megan Megan's 30 She has spinal muscular atrophy and has been on a ventilator since childhood Megan unfortunately cannot sit like the woman in this photo here. Megan is totally dependent for all of her care, but She is witty and smart and can tell you everything that needs to happen for her care Chris is 25 Chris has autism. He has really severe asthma as well with frequent admissions and Given his autism and really significant delay associated with that autism He does not handle that change in his schedule well and cannot understand Painful things like blood draws that need to happen to him And so he fights and he has actually hurt some of the nursing staff When he has fought back with with those things because he just doesn't understand Tiffany is 17. She's got cystic fibrosis with moderate lung disease Her Fe1 sits in like the 60s not ideal, but she does okay from that standpoint, but over the course of the last year It's actually been her opiate use disorder. That's been the biggest problem, and she's been admitted with bacteremia as multiple times So all three of them have very different challenges that are going to be associated with their transition We've been struggling with this adolescent young adult age for a really long time even Shakespeare would have preferred that there were no age between 10 and 23 and We still as a society are not really sure when we consider people to be adults So we say that 14 year olds can stand trial as an adults But you have to be 25 to rent a car without additional stipulations We're not really sure where that falls And that's because there probably isn't a bright white line not that standing trial is an easier thing to do than renting a car but we There's not a clear line and the challenge there is that adolescents and young adults Cognitively perform the same way on simple tasks as adults do However, their prefrontal cortex is not fully developed and that controls a lot of how they behave So it is very normal for adolescents and young adults to not actually be able to understand risk to themselves and so there are some interesting studies of Teenage girls with risky sexual behaviors, and they can tell you like oh yes, I know in this population there's a 15% chance of getting gonorrhea, but I'm obviously not going to get it and That gets really frustrating as we're approaching these behaviors, and that's actually developmentally totally normal for them Adolescents are also much more susceptible to outside influences. So things like Rewards threats peer pressure all of those things loom much larger in an adolescent brain And they haven't quite developed the executive functioning that they need to figure all of these things out And so when we talk to our adolescents and say you need to take all of your medicines And you need to come to your appointments they might not be able to remember hey, I got to bring this with me and Maybe I don't want my friends to see that I'm gonna have to like step away and take some medicine Because they're gonna judge me and I like I don't think it's actually a big deal I know my doctor says I have like really severe lung disease, but like it's fine and That's very developmentally normal for these patients And it leads to this really high risk time in late adolescence and early adulthood So in sickle cell disease we see 50% more ER visits and admissions in early adulthood compared to Earlier in adolescence we see 50% more admissions in CF as well mortality doubles in Young adults with sickle cell compared to earlier in adolescence CF it doesn't quite double But there's a substantial jump in mortality around this time, and there's a pretty substantial fall in FEV1 as well So if we look at like 15 to 18 year olds with cystic fibrosis Almost all of them have an FEV1 that's over 70% by the time they reach 25 That's only 60% of them So we see a really drastic drop in lung function and increase in morbidity and mortality in this group Why is this hard? So I highlighted earlier this kind of not ready to be an adult that we see on the upper left there But there's a lot of other things too So we don't do a great job preparing our patients and our families for this transition We're giving putting them into a new system that they don't already know where they've learned to navigate another system Patients and families and adult providers share this really unclear role of like well What are the parents supposed to do there's legally a change when they turn 18? But there's not like a magic light switch that changes in that relationship pediatric providers and patients and families share that they worry that they're losing this long-standing relationship that they might have had with this patient and family for 20 years and There's this perception that the adult system is less caring and as an adult doctor I can say we care a lot about our patients, but we don't always do the greatest job supporting them So calling to remind them checking in on them about no-shows those sorts of things and that's where a lot of that perception comes from Pediatric and adult providers and Shakespeare don't much like adolescents and young adults. They're a difficult group that take extra time and effort and Then there's this concern that adult providers might not know about some of these diseases Hopefully, you know a little bit more about some of these diseases after today But that certainly exists as well and that exists among the adult providers as well And then as we talked about with Chris There's this extra level of developmental delay and how do we take care of these patients that are chronologically? Adults and even older adults and their bodies are adults and older adults, but they interact like younger children And along those lines, I think it's important to differentiate those patients from patients who are truly neuro devastated and don't interact But they're actually a little bit easier to transition from that standpoint because they interact with the health care system Not dissimilarly to some of our adults who have had catastrophic neurologic events So, how can we do this better? So over the next several slides, you're gonna see some images from CF rise, which is the Cystic Fibrosis Foundation's Transition program as well as got transition, which is a national group that is working on improving transition So what I really want to highlight on this slide is that this should be a very gradual transition of responsibility Not a light switch that flips So this is starting even like school age age like six to nine and I'm starting to take responsibility For medications and gradually increasing that This is the six core elements from got transition And again, this starts with talking to pediatric patients at age like 12 to 14 and their families of saying this is the time that we transition and then we'll focus more on that kind of readiness and planning part of How do we do this in their adolescence? So they're ready when they get older So this is an example transition readiness assessment And these are things that I would never honestly think to ask most of my patients Things like do you know how to get medical care when the doctor's office is closed? Do you know how to refill a prescription? These types of things and these don't need to necessarily be a physician that's completing these But if we don't know that our patients don't know these things then we don't know to teach them I think particularly about youth and foster care or other people that might be particularly high risk for not learning these skills In addition to those kind of knowledge things. We also have responsibilities and so Understanding as adolescence goes along which of these things are people actually doing maybe they say yeah I do my medicines, but like mom sets up the nebulizer and hands it to them and they then they do it How what are they doing? And how can we make sure that they're progressing along that? So when we think about how can pediatricians do better? Proactively discussing the timing of transition. I have a young woman right now who has pretty significant respiratory disease and just was told that she needs to transition because she's pregnant and is kind of panicked that she both is a little concerned about being pregnant as a pretty young woman and Also now she's losing all of the care that she's had in the past all of those providers so we need to be talking about this and when we're gonna do this a long time beforehand and Identifying an appropriate adult clinician. So this should not be that we're telling patients and families like good luck go find somebody but we should be Identifying and really working with our adult clinicians and not only the adult clinicians at the closest academic medical center that we're affiliated with But a lot of these patients could follow much closer to home now that they're adults and are probably more likely to actually show up If we can identify somebody that's close to their area if that's appropriate for them We should on the pediatric side not just send your last clinic note that might or might not have a lot of detail or kind of information about their course But be sending really a full medical summary and ideally communicating directly with that person On the adult side same thing communication. We should be communicating back with pediatric providers Saying proactively if you are interested in taking care of young adults I think every pediatric pulmonologist out there would be thrilled to hear from you that that's something that you might have an interest in doing and that you're willing to kind of take the time and effort that it can take for these patients and then Communicating back and saying hey, they came to their first appointment. Here are the questions that I have This should be an ongoing conversation between those two providers, which is certainly difficult in many of our more fragmented health care systems Actively welcoming our young adults into adult care oftentimes They get this message of I don't much like nineteen-year-olds. I'm a little afraid of you So saying we're really glad you're here. We know this transition can be really hard Then talking about hey, here's how you request a refill Here is how I am or am not going to communicate with your parent if mom calls to schedule an appointment I'm going to say okay, or I'm gonna say no you need to do that and being really upfront with them And again, this doesn't have to be necessarily the physician that's doing these things but this is an important part of really making the adult feel like they have a medical home and Then doing the same thing that we talked about in our adolescence to a self assess self-care skills and disease specific knowledge That if you're having an adolescent or young adult that is not doing the things that you think they should be doing to take care Of themselves then using some of those readiness questionnaires that we talked about and maybe you can identify some big gaps That you can then actually educate them on and improve their access to care and their ability to care for themselves So thank you all so much for your attention Please do evaluate our session in the app, and I know we are a few minutes over I think we're all we'd all happy be happy to answer questions But certainly understand if folks have other places to go as well. Thanks for your attention You

respiratory illnesses

cerebral palsy

management

mortality

motor function

risk factors

aspiration

airway clearance

chest physiotherapy

sleep disordered breathing