Hello. Welcome, everybody. I'm Aileen Tee. And then I think, thank you for coming to our presentation. I think this is a really important talk since the care of CF has changed over the past couple of years. So if someone could close the door so we can get started. Thank you. Okay. So I'm going to introduce Sarah Chalmers. She's Med-Peds from the Mayo Clinic. And today she's going to be talking about the new diagnosis of cystic fibrosis in adults. Good morning. So like we said, I'm Sarah Chalmers. I'm on staff in the adult clinic in pulmonary and critical care at Mayo Clinic. And I have the Med-Peds training background and I have no disclosures. So when we're talking today, so cystic fibrosis has absolutely exploded over the last decade or more. And we've learned so much about the disease, about the genetics. And that might change how we want to think about cystic fibrosis in the adult. So when I'm talking today, I'd like you to kind of picture yourself in an adult clinic. You get a patient, they come in, and they have bronchiectasis. And this is the first time they're hearing that. And so what you're going to try to decide is should I evaluate this patient for cystic fibrosis? And I'm going to start by doing a little show and tell, a couple of cases. So the first is, was a 43-year-old male. He came to our clinic with two years of cough and shortness of breath. He had told us that he had had asthma for as long as he could remember. He had allergies with a lot of upper respiratory symptoms and he had recurrent pneumonia for the first time starting at age five. He was slow to grow being under five feet and less than 100 pounds by his freshman year. And both parents were of average height. On exam on that day, his BMI was 30. So he was a little overweight. He had big, boggy nasal turbinates. He had coarse breath sounds bilaterally. He had fixed obstruction, just mild on his PFTs. He had some lab findings that were suggestive of a little bit of atopy. The rest of his workup for bronchiectasis for an underlying cause was negative, including ABPA and immunodeficiencies. And his CT scans showed sort of, if I could roll through the whole thing, it showed a little bit of diffuse bronchiectasis, but more in the upper lobes. At that time, he actually was given a diagnosis of asthma. And it was thought that his bronchiectasis was maybe related to longstanding, poorly controlled asthma. He got optimization of his medications for his asthma, but really with no improvement. And it was actually the patient himself who had started nursing school and was learning about cystic fibrosis. And he said to his pulmonologist, he said, do you think I could have cystic fibrosis? Maybe we should test. And they tested him with sweat chloride, and they came back grossly abnormal with a sweat chloride of 101 and 100. And then did the genetic analysis, and he was found to have two CF-causing mutations. So symptoms plus a positive sweat chloride, two gene mutations. So he met the criteria for cystic fibrosis and was given that diagnosis. So I think when we think sometimes back to medical school, and we think about what did we learn about cystic fibrosis, we think about it as a multi-organ disease. We think about it as a severe disease manifesting early in childhood, causing sinus disease, bronchiectasis, pancreatic insufficiency, and a lot of comorbid conditions that go along with that disease process. And we think about rapidly progressive or progressive lung function decline, and maybe needed a transplant in their 20s, 30s. Our patient here, this 43-year-old, had lots of symptoms that could be consistent with cystic fibrosis, right? He had the sinus symptoms, the bronchiectasis, the recurrent pneumonia. He had sort of this failure to thrive-like picture as he was growing as a child. And he had asial spermia, which, by the way, did not undergo further evaluation to find an underlying cause. So it certainly could see you how this patient maybe should have been screened for cystic fibrosis. But let me show you a less obvious case. So my second one is a 72-year-old female who came in for second opinion of her bronchiectasis. She actually was pretty healthy up until adulthood, where she was diagnosed with rheumatoid arthritis and GERD. So of course, we have some things that could be causing her bronchiectasis right there. And then she also had had recurrent NTM disease. She'd been treated for NTM twice over the course of 20 years. So we had another cause, possible cause, although the temporal association of NTM and bronchiectasis is not clear. But maybe that was the cause of her bronchiectasis. This is her CT scan. It's the only one I have, so please ignore the pneumothorax. But she had big varicoid and cystic bronchiectasis. And it was middle lobe predominant and to a much lesser extent in the upper lobes. So this was starting to screen. Maybe this is NTM related, right? And she's a thin lady. She's in her 70s. So NTM was really thought to be the cause of her bronchiectasis. Her evaluation for underlying cause was normal. She's not even growing NTM at this time. She's got growing MSSA. So there was a lot of discussion about should this patient be screened for cystic fibrosis? Well, if you look at the screening guidelines, so their consensus statement, the most recent one we have is from ERS, put out in 2017. And it recommends screening for underlying diseases in the first time that you see a bronchiectasis patient. Screen for diseases that will change the way that you treat the patient. So we look for immunodeficiencies. We look for ABPA. Sometimes we do sputum cultures and we look for NTM. But what do they say about cystic fibrosis? When do they suggest we screen for cystic fibrosis in our adults? They suggest that if it's a young adult or they have features to suggest a cystic fibrosis such as upper lobe predominant bronchiectasis, polyploid sinusitis, recurrent pancreatitis, infertility or malabsorption. But I'd like to point out that our 72-year-old would have been missed if we had followed these screening guidelines. Another thing I think I commonly hear in the adult world is, well, cystic fibrosis should be picked up on a newborn screen. And I think this is just a lack of understanding without exposures to some of the pediatric world, that newborn screening really hasn't been around that long, right? So the first newborn screen for cystic fibrosis was in Colorado in 1982. And then over the next decade, four states picked it up. But it wasn't until 2010. That means that it was widely distributed across the United States in all 50 states. That means any patient that you see that is over the age of 12 perhaps did not have a newborn screen for cystic fibrosis. So certainly don't rely on a newborn screen to pick it up. In addition, there is potential for false negatives. So IRT, the serum marker that we use to screen for cystic fibrosis, has false negatives. And some of those things that lead to false negatives are a stressful birth or meconium ileus, things that we often see in our cystic fibrosis population. Sweat chloride testing in the newborn is no cakewalk either. There's lots of room for error in sweat chloride testing. So again, cystic fibrosis diagnosis could be missed in childhood. So I talked a lot about, or I talked a little bit about how we've learned a lot about the genetics. So if we think way back, Delta 508, that's our classic mutation, right? And we used to think a long time ago that that was the only mutation. But we've learned a ton over the last decade or more. And now we know that we have identified 2,000 mutations on the CFTR. And 200 to 300 of those are thought to be clinically relevant. This, and if you look at the picture here, we see that some of these mutations may cause a more severe disease. And some of these may cause a milder disease. But remember, it takes two mutations to cause disease. So you could have any combination. So you could have one severe and one mild. Or you could have two severe, or you could have two mild. And there are other factors that play into phenotypic expression as well. So you could have a patient that has only one organ involvement. Perhaps they have bronchiectasis only. You could have a patient that has sinus disease. You can even have a patient that has isolated absence of the vas deferens. So this is the diagnostic algorithm. This was published in the Journal of Pediatrics in 2017. And I don't know that a lot of adult pulmonologists are reading the Journal of Pediatrics. So I'm not going to go through it step by step. But just to point out that the diagnostic criteria would say that you need symptoms, you need to demonstrate CFTR dysfunction, and you need to have two mutations. Now, the two mutation criteria gets a little sticky, right? There's a lot of mutations, and they don't all cause disease. And if you look in the center there, you can see it talks about CF causing mutations and other types of mutations. But that's no need to worry, because there's a tool to help us with this. So the CFTR2 is a collaboration by the Cystic Fibrosis Foundation and John Hopkins. And this is an international database with over 90,000 people represented that has looked at all of the genes that have been identified and classified them into these four categories. Either CF causing mutations of varying clinical consequence, meaning maybe if they're paired with the right CF mutation, a CF causing mutation, they might cause disease, uncharacterized, or non-CF causing. So our first patient, this is actually his genetics. So those are his two genes that I plugged in. And you can see you get a lot of valuable information from this. We see down in the bottom in bold that these two variants in combination cause cystic fibrosis. And we see also that these patients are likely to be pancreatic sufficient, which is our patient with a BMI of 30 and no GI symptoms. It'll tell you a little bit about the sweat chloride, what do you expect it to be. It'll talk about the percent of patients with pancreatic insufficiency with this combination, the patients that have pseudomonal infection. And if you look in the middle, it'll even tell you which protein modulators these mutations qualify for. So a very, very useful tool. Sometimes in the adult world, I'll even hear things like, does making the diagnosis of CF matter? Is it going to change this patient's outcome? And I would argue, yes, it definitely matters for multiple reasons. You think about that cystic fibrosis went from a life expectancy of eight to a life expectancy of near 40 just by standardizing the care, along with a few other things. But cystic fibrosis foundation got together, organized, standardized the care of patients, and life expectancy profoundly changed. So simply classifying them as cystic fibrosis and having them cared for in a center that is familiar with their care can be very impactful. And then, of course, there are some medicines that we use to treat cystic fibrosis that we don't use in non-CF bronchiectasis patients. But probably the biggest reason and the easy sell is that I have these, right? So if I have a patient who qualifies for a protein modulator and they have bronchiectasis, I can substantially impact, potentially substantially impact their quality of life and potentially their life expectancy. These are new medications. We're going to hear more about them later. And we have a lot to learn. But I can tell you clinically, we certainly see a lot of improvement in our patients. So our second patient did go on. She had a positive sweat chloride at 61 and 62. And she had two CF-causing mutations. So at the age of 72, we made the diagnosis as cystic fibrosis. Both of those patients got started on Trikafta, and both have had substantial clinical improvement. So I wanted to impress on you today that in the adult, we are no longer just diagnosing CF in pediatrics. And it's important to pick it up in adulthood. You need to have a high index of suspicion. And you need to, in order to make the diagnosis, they need symptoms, CFTR dysfunction, and two mutations. Thank you. That was a great talk, because I think, you know, we don't think about diagnosing CF in the adult world, or in adults. I think it's all PD. But I mean, I've known that we've had, I think our oldest was 62 or so when we diagnosed. So next up, I'm going to introduce Douglas Hornick. And he's going to be talking about, I guess, non-pulmonary manifestations of cystic fibrosis that we need to know. Thank you. Yes, I'm Doug Hornick. I'm from the University of Iowa. I'm the CF Center Director at the University of Iowa. And I just lost everything. Oh, there it's back. Thank you very much. So isn't it great to be together in person again here in Nashville? I have no disclosures that are relevant to this particular talk. And I've been given the job to really cover the non-pulmonary manifestations of cystic fibrosis. That includes DIOS. How many of you know what DIOS is when I say that abbreviation? So it's distal intestinal sub-obstruction syndrome, sinusitis, and pancreatic insufficiency. And so basically, we're going to be asking you to think outside the box, if you will, for this particular segment of the session. So the objective, then, is to manage these common non-pulmonary manifestations or basically thinking outside the chest, if you will. Pretty cool, huh? So as we already heard from Sarah, this is a multi-organ system disease. So it stands to reason, then, that we're going to have disease in some of the other organs at times. Particularly seems to show up when they're inpatient for exacerbations. So I'm going to focus on the sinusitis, the pancreatic insufficiency, and distal intestinal obstruction syndrome in the GI tract, along with colon cancer. And I'm going to do this also in a case-based approach. So you're the pulmonologist. You have a colleague who does all the CF, so you don't have to worry about it. But he decided to take off to the Himalayas for a three-week trek to try to climb Mount Everest. So he's not going to be reachable over the next three weeks. And his parting words, they're all in Trikafta now. You don't have to worry. You know that doesn't always work out, does it? And so there are 10 percent of people with CF for whom the modulators do not improve disease. And this is one of the patients that showed up the day after he left, and he needed to be hospitalized for an acute exacerbation of his pulmonary disease. So you're responsible for his care. So this is a 42-year-old male with cystic fibrosis who now has a shortness of breath, cough, and sputum reduction. And then the nurse calls you on the second day and says he now has a frontal headache, 11 out of 10 severity. Do you want to treat his sinus infection too? So you go see the patient. He does have pretty significant nasal congestion and a frontal headache. No photophobia or neck stiffness, good thing. But he does have lots of purulence in his nasal passages, boggy nasal mucosa, and maxillary sinus tenderness. So it looks like he has acute sinusitis as well. And so sinusitis is relatively common in CF patients, particularly chronic sinusitis. The patients actually say, you know, that they just live with the symptoms. Ninety percent demonstrate panopathification on their CT scan. The bacteria that you isolate from the sinuses are very similar to the bacteria you isolate from the lungs, so there's really no difference there in terms of the antibiotic coverage. Thirty percent develop nasal polyps. The ones that are homozygous for the most common mutations, 65 to 70 percent, 508 del homozygous, they're associated with worse sinus exacerbations, and they have the hypoplasia in the frontal and the sphenoid sinus. But still, there's no correlation with the severity of the sinus disease and their FEV1 outcomes. The treatment recommendations now have been developed into a consensus and published just this past year, and the treatment recommendations are nasal saline, irrigation, and topical nasal steroids. Only sinus surgery in those extreme cases that can't be managed medically. And of uncertain benefit are multiple things that have been tried such as steroids, DNAs through the nebulizer through the nose, dilute baby shampoo. But over the last couple years, three years really, there's been increasing data published that showed that once these patients start on CFTR modulators, their sinus disease becomes much better, and particularly with the Trikafta, and less problematic. So I hope you're not too sick of this non-pulmonary stuff. We are close to Halloween, and it's pretty scary. So we're back to the patient again, and it's day four. And his sinuses and his lung disease are better, and that nurse calls you again. Says now he has abdominal pain, 11 out of 10 in severity, and no stool output, by the way, for the last 48 hours. Now you remember that CF patients have some constipation sometimes, so you go see him. He's nauseated. He does have very intense pain that he points to the right lower quadrant. His abdomen feels bloated, he says, but it reminds him of an event that he had in the distant past where he was told he had a bowel obstruction. When you examine him, his abdomen is distended, and the pain does localize right to the right lower quadrant, and there's no rebound tenderness, and you can't hear bowel sounds, but they're present but diminished. So what do you do now? This doesn't seem like pure constipation. So you check a KUB, and you see air fluid levels. So your eyes get a little bigger, and you note accumulation of stool in the ileocecal region. So what do you do now? The patient and the nurse are waiting for you to give some advice. So you're suspecting this entity called distal intestinal obstruction syndrome. So what do you recommend? Just pretend you have the audience response system right here. Would it be called GI? They can get you out of trouble with a colonoscope. Call GI surgery to relieve the bowel obstruction. Give them polyethylene glycol osmotic type laxatives or convert to a high fiber diet and encourage exercise. Which would you do? Anybody yell out one, two, three, or four? That's the audience response. Good. Thank you. Everybody's saying number three, Dr. Hornick. That's right. So you know this is distal intestinal obstruction syndrome, so you recommend the osmotic laxatives with polyethylene glycol, the first line regimen for DIOS. And he gave you a hint, and it's history, right? Because prior obstructive events are very predictive of subsequent DIOS events, and it is actually fairly common to have DIOS in CF anyway. 10 to 47% of the patients will do so. In terms of converting to a high-fiber diet or encouraging exercise, that's good for constipation, but not good enough for distal intestinal substance syndrome. I do want to point out that the surgeons often recognize this as an obstructive event and want to take the patient to surgery, but in fact, they need surgery to relieve the obstruction less than 5% of the time. So it's better to hold back the surgeon and avoid those complications, potential morbidity. And the GI physicians are not at all interested in doing a colonoscope on these patients. So this is the patient's flat plate. And so let me drill down on some of the clinical features that will help you discern that this is indeed an episode of DIOS. They have moderate to severe abdominal pain that localizes to the right lower quadrant with or without distention. They have intestinal obstruction, and they sometimes will be vomiting bilious material, but they're certainly always nauseous. You can feel a fecal mass in the iliosecal region, and the KUB shows that evidence of small bowel obstruction where the asterisk is showing the air fluid levels in the small intestine, and then the orange arrow is showing the right lower quadrant impacted mucofeculent mass that you can sometimes populate on physical exam. If you take the patient to CT scan, the CT scan is a good idea to rule out other causes of obstruction if you're uncertain, and it usually confirms your KUB findings. But let me point out that every CF patient almost has an enlarged appendix. So the surgeon will see that and want to take the patient to the OR. But in fact, it's a common finding, and without added inflammatory changes, the fat stranding, the fluid, and the other things you can see on ultrasound or CT that confirmed appendicitis, they don't need their appendix taken out. So what about if it was just plain constipation? How do you know when it's only constipation versus a diose episode? Well, it's just a less severe episode. Their appetite is definitely poor, and they have discomfort, but it's not as intense, and it's not localized to the right lower quadrant. They will complain of gas and straining with passing stool, and they'll describe their stools as harder than usual, lumpy, et cetera. I could go into detail if you want, but I'll just pass. The exam can show palpable stool and tenderness that's diffused throughout the abdomen rather than just localized in the lower quadrant. And the KUB shows the small intestine has stool throughout without any air fluid levels. And I demonstrate this. This is an example from one of our patients. And you can see the stool is present throughout the colon shown by the asterisk there. So you should always, with an acute abdominal event, consider all alternative differential diagnosis and not jump just to diose or constipation. So considering the CF patient, again, the acute appendicitis is always in the differential diagnosis, but enlarged appendix is not that diagnosis. You need to have the surrounding signs of inflammation to require the appendix coming out. They can also get proximal or distal volbulus. Medications can induce obstipation, such as certainly if they've been on narcotics for their pain. I've seen atypical presentations of C. diff present with abdominal pain that mimics diose. And certainly C. diff is a little bit more common or somewhat more common. Actually, it's not that common in CF, but they're at risk because of all the antibiotics that they get. The other rarer things are inflammatory bowel disease, malignancy, and if they get too many enzymes, they get this entity called, pancreatic enzymes called fibrosin colonopathy, but it's very uncommon. Small intestine, you also have to think about intussusception, obstruction from adhesions, prior surgeries, or hernia. Medications, again, and the rare things, inflammatory bowel disease or malignancy. So, the management of diose is to initiate supportive measures, as I mentioned, in addition to the polyethylene glycol. So, you give them volume, IV, their MPO, you replace the electrolytes as needed, IV, andangetron, consider giving a prokinetic with metoclocopide at pain control, but limit the opiates, and certainly have the surgeons on board, but again, remember that they get through this 95% of the time, and it's good to have them around just in case it's one of those rare events. Now, another key fact that is helpful or important to sort of discern in these patients is whether or not there's air fluid levels on the abdominal flat plate, or the CT scan, because if there are, it's probably better to do NG suction from the get-go to decompress, start with the gastrographin amino from below, followed by go lightly via the NG tube from above. If they don't have the air fluid levels, then you can sometimes start with PO, but many of these patients are so nauseous that you need to go with an NG tube, and if they don't respond, then go to the enemas, your GI radiologists appreciate it when you try everything else before you send them down for the gastrographin. Note that the contrast, oral contrast given by CT scan has an osmotic laxative effect, so the CT scan with oral contrast can not only be diagnostic, but can also be therapeutic. I've had that happen on several occasions where the patient comes back and says, wow, I feel much better. I passed stool when I was on the way back from the CT scan. So you repeat these cycles of go lightly until you get clear effluent from below. So for our patient, back to the patient, the symptoms resolve after an enema and four liters of go lightly. You take out the NG tube, now you start them on Miralax at least three times a day, titrate up and down to encourage PO fluids, advance his diet, emphasize adherence to the pancreatic enzymes with meals. So we're not to the end yet. Sorry about the end there. So inpatient management of pancreatic insufficiency is important as well when the patients are there. For pancreatic enzyme replacement, I mentioned that already, the dose is shown here. You also need to check and replenish fat-soluble vitamins A, E, K, and D, maintain a higher caloric intake than you would for a general patient. These patients have a higher metabolic rate and require up to 150 to 200% of the daily caloric needs. It's helpful to have a dietician advising, particularly one that knows about CF, can help you with prescribing appetite stimulants, keeping track of their caloric intake, and getting the dietary department to send sufficient numbers of calories. These patients eat a lot. Enteral nutrition, when they don't, aren't able to get it, usually that's more of a chronic intervention, and since TRIKAFT have been less, much less common. FEV1 outcomes are tied to the BMI pretty closely. So we try to keep, there's a break point at a BMI of 22 for females and 23 for males. So those are the targets. So after discharge, this CF patient would end up in your clinic, of course, and his sinus and GI symptoms have now resolved. His BMI is where it should be. His FEV1 is at baseline. He's there with his wife, and she asks, what about colorectal cancer screening? He has no family history, and so you think to yourself, well, CF patients are living longer these days, so colorectal cancer screening should be starting about 45, just like everybody else, right? Well, actually, colorectal screening should start earlier in the CF patient at age 40, and this guy being 42 should have already had his first colonoscopy. So the risk for colon cancer is higher in CF. It occurs at a younger age compared to the general population. Polyps develop earlier and progress more rapidly. 20 years earlier at onset than normal, about age 40 in CF patients, and the ratio incidence compared to the general population is about six-fold. The risk factors, the men are more likely, and homozygous with F508-Del, and being over the age of 30. So we now have consensus guidelines published about four years ago, and so the recommendation is for colonoscopy to start at age 40 in all CF patients, younger in transplants because of immunosuppression, and also the interval is more frequent than the general population because of the increased risk. So I've described to you a 42-year-old pulmonary exacerbation case that demonstrates the multi-organ system involvement that often complicates the inpatient management of these patients. Acute sinusitis and distal intestinal obstruction syndrome respond to medical management fairly well and rarely require intervention by the respective surgical specialties, as I pointed out. DIOS will mimic acute appendicitis, and remember that it's normal for a CF patient to have an enlarged appendix on the CT scan. You need additional inflammation for it to be appendicitis. The findings, though, of DIOS localize to the right lower quadrant to mimic appendicitis. Your physical exam will show more of a mass-like in that region, a feculent mass in distinction. So the patients respond to supportive care, osmotic laxatives, particularly a polyethylene glycol. Alternative abdominal diagnoses are important to consider in any case, so keep in mind intussusception, bobulus, and C. diff. Nutrition is important in CF patients, as much so today as it is for slightly different reasons with Trikafta, but still important, and they still need the fat-soluble vitamins A, E, D, and K. And colorectal cancer, remember, starts earlier in CF patients. Now they're living longer. As was pointed out by Sarah, the population of CF has doubled in the last 20 plus, or 30 years, because 60% of them now are adults, and they're living longer, and the last estimation is the median survival was in the 50s. So with Trikafta, there's been a huge difference. So you're going to start seeing patients like this, probably in your general clinic, less tethered to CF centers than in the past, perhaps. So thank you very much. I hope that wasn't too scary outside the chest. Thank you. Thank you, Dr. Hornick. For our next two talks, I wanted to remind everybody we are actually using the audience response system, so if you can get out your chest app, your chest events app, and sign in, and you can use the app to answer the questions. So you'll scroll down to the session, and it'll have a polling link at the bottom, and then you'll click on that for using the audience response system. So I wanted to introduce Holly Keet to talk about pulmonary manifestations, laboratory monitoring, and imaging for the general pulmonologist. Okay. That was good. Thank you. Well, good morning, everybody. This is just about my favorite thing to talk about, CF, bright and early in the morning. So I am the Director of the Lung Transplant Program at our institution at UT in San Antonio, but before I had that role, I directed our adult CF program, and now I love to go to CF clinic because all the patients are having babies and doing great things with their adult lives. So we're gonna talk just a little bit about what it looks like to monitor these patients, on kind of a chronic basis. You've heard from my colleagues already this morning about the multi-system effects of CF, and why it's important that we need to monitor these things, but we're gonna start out with a case to make sure we're all awake. So this is kind of a real thing that happened to us. Our CF center is located in South Texas, and below us, so all the way down to the border and west of us, there are no CF programs. So we've got patients extending all the way out to El Paso, which is like an eight-hour drive from us, down to the valley, and so a lot of them have a hard time getting to us, especially in the midst of a pandemic when travel is a little bit more challenging. So the case in front of us is a 43-year-old woman with CF who presents to your general pulmonary clinic for follow-up. She's also followed at the CF center, but it's 300 miles away. It's hard to get to, and because of difficulty with travel, she hasn't been seen there in more than six months. So she comes to your clinic and reports an increase in cough and a little bit of yellow sputum production and occasional wheezing. So the question is, what do you do next? So options are, do you tell her to call the CF clinic, have a nice day, prescribe a Z-Pak, and ask her to follow up, get some additional testing, or admit her to the hospital for a tune-up? Excellent. Given the topic of this session is testing for these patients, that's probably the right answer. Okay, so as you've heard from my colleagues, CF is a multisystem drug. As you've heard from my colleagues, CF is a multisystem disease. These are some results from some of the patients I've taken care of over the years, showing a patient who had endobronchial, or sorry, bronchial artery coils placed by a cardiologist actually before they met me for massive hemoptysis, patient with severe sinusitis, osteopenia is what that DEXA scan shows, patient with DIOS, which has the typical imaging findings that you just saw in the previous talk, as well as patients that we monitor for diabetes and liver function abnormalities with their testing results there. So you can see that these patients have a lot of problems that go over the years, and even though modulators are now online, and a lot of them are doing more adult kind of things and living pretty healthy lives, there still are underlying things that we need to be monitoring for. So starting out with blood work, this is kind of the routine management for our CF patients. So we get a CBC with differential looking for signs of anemia, which could point to potentially undiagnosed colon cancer. We want to monitor their EOS counts, looking for atopia or potential signs to ABPA. Also, some of these patients will develop a thrombocytosis when they're acutely infected, and so getting a CBC will point to that. We monitor their liver function tests, and particularly GGT, which is more sensitive in CF patients for evaluating the cholestatic picture that tends to happen with these patients. We monitor their IgE, their fat-soluble vitamin levels. We try to get them to do a oral glucose tolerance test annually, but I don't know if anybody else here runs a CF program, so it's a little bit hard to get patients to come and do this and drink the terrible stuff and sit there for a couple of hours. But it can give us a clue that they're in the process of developing diabetes or some glucose intolerance. And then we monitor their A1Cs, which are not as accurate over the long term for these patients as they are in the general population, because there's a more rapid turnover. And then we check a urine microalbumin for patients with diabetes. As far as sputum cultures, this is one of the very important things that we do. We get a sputum culture every time someone comes to clinic. And they should be done at least annually, but preferred quarterly per the CF Foundation guidelines. Throat swabs have not been validated in adults with CF. However, we use them routinely because, especially now that they're all in modulators, a lot of them are not really producing sputum. And we try to have an idea about what kind of bugs they grow chronically, so that way when they get infected and they come into the hospital, we have an idea about what to treat them with right off the bat. Labs that are performing these, the testing on these sputum cultures should be familiar with doing this, should be familiar with being able to identify the multiple different strains of pseudomonas that they'll have growing, and being able to do susceptibility testing for antibiotics. Cultures for NTM should be performed annually because rates are higher in people with CF than the general population. And anyone with a confirmed or suspected Burkholderia sepacia complex should be sent to a reference laboratory in the United States, which is at the University of Michigan. As far as imaging goes, we don't want to expose these people to unnecessary radiation, but it is important to keep an eye about what's going on in the chest that we can't just hear with a stethoscope. And so the CF Foundation recommends getting a PA lateral chest X-ray every two to four years in patients who are stable. And for those patients with kind of mild disease or early on, it might look pretty normal. Or they might have some hyperinflation, they might have prominent bronchovascular markings, they might have advanced cystic changes. You can see on the top kind of course, you can see airway thickening, there's some mucous impact in some of those airways. I don't know if you can pick it up. And then in more advanced disease, tends to involve the upper lobes and have that peribronchial cuffing. On the bottom, you can see an X-ray from a patient on her left that has the finger and glove typical pattern of AVPA. Looks like someone put a handprint on her chest. But there's other reasons to get X-rays too. So if someone comes in with acute symptoms, getting an X-ray might point to something going on. So the first X-ray that you see there, these are all patients who had some complications of CF, shows complete right middle lobe collapse, which can happen in these patients if they get a more central airway obstruction. And then on the left was a patient that we saw, or sorry, in the center was a patient that we saw who came in with just kind of like exacerbation symptoms, very similar to the case that I presented. Turned out to have this big abscess in the left upper lobe that was MSSA. And then on the bottom there, you can see a pneumothorax with a chest tube in. As far as pulmonary function testing goes, this can be done starting really early in childhood. Kids in grade school age can start doing reliable pulmonary function testing. And in our clinic, it's kind of fun, our adult and PD clinics are in the same place, although we don't have clinic on the same days. It was really fun to hear the respiratory therapist working with little kids and talking about blowing out candles or blowing up balloons and things like that and learning how to do PFTs. So they start doing it from a very young age and by the time they get to adulthood, generally can do it pretty routinely. We monitor them at least every three months and of course when people have symptoms. But also over the last couple of years, we've started monitoring PFTs in people at home and patients are very good at doing this now. They can remotely send their PFTs to us so that even if they can't see us, they're hundreds of miles away, we can at least know what's going on with their lung function. Typically they have an obstructive pattern, but that's not always the case. And of course if there's an acute change, it might indicate an exacerbation going on. This is just a representative example of one of our patients with an obstructive pattern of spironometry. Of course there's other ways to monitor pulmonary function, including lung volumes, pheno, and importantly for people who have advanced lung disease, some physiological monitoring of gas exchange. So obviously we check pulse ox every time patients come to clinic, but for people who have advanced lung disease, which the CF Foundation has specific guidelines to define, should have a six minute walk test every year. They should be evaluated for hypoxia during sleep, as well as monitoring for the presence of hypercapnia. All of these are pointing to the idea that patients have more advanced lung disease and might need a referral to a lung transplant center if that's something that fits with their goals for their life. You heard a little bit about cancer screening already, but CF doctors tend to be these patients' primary care doctors because they get to know the team so well. They come and see us every three months for most of their life. And so it's really important also to have a mind for the things that happen to these patients now that they're living well into adulthood. And pretty soon, we're going to be doing geriatric medicine for CF, which will be really exciting. But for now, we need to keep an eye out for colon cancer screening, reproductive health and fertility, which is a very hot topic with the Trikafta baby boom, bone and joint disease. DEXAs should be obtained for all adults with CF at least once and then depending on the results. As well, mental health is a big problem. Or access to mental health care is a big problem in the United States. We all know that. And people who have chronic lung disease particularly are at risk for depression and anxiety. And so we try to screen all of our patients every time they come to clinic and actually have a psychologist that works as part of our team who's integrated and can provide mental health care. And then, of course, vaccinations, which are a hot topic now over the last couple of years, but routine vaccines, too, in addition to COVID vaccines. So that's a lot of information. It's a lot of detailed information to keep track of. The good news is that the CF Foundation has a great resource on their website. They have their clinical care guidelines, which address a number of different topics, including adult-specific care, and even better, a really quick and easy to access summary so you don't have to read through all those pages. And actually, I did this a couple of years ago, so I have to put a plug-in for it. So you can just go to the website that is linked there. You can scroll down to the section that you're interested in, and there'll be a hyperlink to the guidelines specific to that topic. So that's easy to keep an eye on when your patient is in clinic and you don't want to flip through 30 pages of guidelines. So by way of summary, monitoring these patients involves quite a few tests that we do on a routine basis over and over and over again. But they're important because we've already discussed the multi-system impacts of cystic fibrosis. And the CF Foundation provides a great resource and keeps it up to date. And so anytime you have a question about this, you don't have to memorize any of this. You can just go to the website and take a look. Thank you very much for your time and attention. Thank you. So I have the job of ending our talk. And I think I have the most exciting topic, which is going to be review of the CFTR modulators, which has really been a game changer for CF care. So I'm Aylan T. I'm currently the adult director at UT Health in San Antonio. For today, I wanted to talk about the modulators itself. We have to go back to talk about cell biology and what the CFTR protein does. And then we'll talk about the mechanisms of the CFTR modulators, discuss the current modulators that are out, and then things that are important to look at, such as drug monitoring, interactions, and then side effects. So in the beginning, this is kind of what the CFTR protein looks like, which looks really cool and complex. How I like to think about it is pictured on the right, that it is kind of a fancy ion-pore channel that embeds itself into the cell surface. And we'll talk about the kind of functions that it does. So the function that we know more commonly that we've learned about in school is that the CFTR protein works for chloride efflux. And then it works for bicarb, and then controls pH from that. And so when it's abnormal, you get a reduced anion transport, which then dehydrates the cell surface. And you get mucous abnormalities, and then in turn, infection, inflammation, and lung injury. And then when they looked at the CFTR protein, it also was really important in causing inflammation, and then regulation of the ENAC system as well. So when it's abnormal, there's hyper-inflammation, proteomic stress, and then impaired innate immunity which then leads to the same infection, inflammation, and lung injury. And then when you get hyper-reabsorption of sodium due to dysregulation of the ENAC system, it also further then reduces the hydration of the cell surface, and then increases mucous abnormalities as well, and then in turn, infection, inflammation, and lung injury. So looking at the CFTR modulators, it's really important to think about the classes of mutations, and then learn about how the modulators work. So for class one, two, and three, these are the most severe phenotypes. So class one, there's no protein that's made because there's a stop codon there. So these patients are really limited with treatment because it goes down to actually probably needing gene editing techniques. Class two is where the protein in itself is misfolded in the Golgi apparatus. And class three is where the protein gets made and goes up to the cell surface, but that protein doesn't work at all. And then in class four and five, the protein's there. It may or may not work, but when it does work, it works less efficiently. So you still get manifestations. And so if you think about it for the class four and five patients, they may have less severe phenotypes, like being pancreatic-sufficient, having milder lung disease, and et cetera. So to talk about the mechanism actions of these products, so you have to think about how the CFTR protein is made. So going back to cell biology, you start with DNA, which then gets read up to mRNA, and then the ceribosome reads that and makes a protein. That protein gets trafficked up to the cell surface, and then that protein, since it works as an ion-poor channel, then opens for chloride to come out. So areas that we can target would be potentiators, which how those work is that they attach to the protein in itself to then actually open up that cell or that pore to help the chloride come out. Correctors, where we can actually have them come in, help those misfolded proteins fold correctly, and then it also helps traffic those proteins up to the cell surface so that they're available. Other things that we can work on are read-through compounds, which will help the ribosome then read through and make the protein correctly. There's also RNA therapies and then gene-editing techniques. So out of all these things, what do we have? So we have potentiators and correctors currently, and then there's a lot of research for the other products. So if you remember, these classes of mutations, so where the potentiators and correctors can work would be actually class two and beyond. Okay, so ready for our audience response system. So knowing what we know, what percentage of CF patients qualify for modulators? That'd be A, 10%, B, 50%, C, 80%, or D, 100%. Perfect, so around 80%. So it's actually more than that. More recently, one of the medications got approved for younger and younger. And so we're more around almost 90% at this point. And then so I thought like this schematic, and so it looks at the availability of modulators for our patients starting from 2014, which you can see is only about 7%. And the latest data that we have from the CF Foundation is from 2020. And so the availability for modulators has really increased. And so you'll see a lot of our patients on this. Okay, so knowing how the modulators may work, what do you think would be the benefits of CFTR modulator therapy? So would they improve FEV1, cause decreases in pulmonary exacerbations, increase in BMI, or all of the above? Yes, 100%, all of the above. So what kind of therapies are out there? So the CF Foundation has a really great area where they show what kind of research is out and where they are in phases. And so currently we have four different modulator therapies that are currently approved and out to the population. But as you can see, there's more and more research being done, and there's things that are pretty close to kind of going out to patients. So I wanted to kind of talk through the CFTR modulators cause I think it's important to kind of learn the history of them. So the first modulator that came out was Ivacaftor, known as Kalydeco. And that was for class three gating mutations. The more common one is the G551D mutation. And what that is, is a potentiator. So as you remember, the potentiators come in and attach to the protein itself to help it open. And so this was really great. It helped with all the proteins that worked. And so it showed really great improvements in FEV1 up to 10.6%. And it reduced exacerbations about 55%. And initially when this came out, only a small percentage of patients had gating mutations that qualified. But now it's really available, and the age for approval is now four months and above. So if you can imagine starting these patients that early in their CF journey, then we may not be seeing any of the late or advanced disease states in the future. Which, like you know, Dr. Keith said, we are gonna be geriatricians someday, which is great. So after that, you know, since it only was for gating mutations, we really needed to target the biggest population, which is the F508, which is the class two mutation. So what they did is they took the potentiator Ivacaftor and added Lumacaftor, which is a corrector. And this was known as Orkambi. And so as you remember, the correctors will then help make more folded protein correctly and then go up to the cell surface. And then potentiator will then go in and help that protein work. And so you would think this would have great effects on FV1, but it really didn't. So it increased FV1 about three to 4%, reduced exacerbations about 39%. And why that is, is that these two molecules actually competed against each other. And so you're actually getting less kind of effective therapies. But I mean, hey, this was better than nothing. And patients would take it regardless. And so this currently is approved for recently, like last month, was approved for one year and over. Because these compete against each other, they do cause a lot of side effects, such as chest pain and shortness of breath, which then these patients can't really tell if they're having side effects to the medication or if they're having a pulmonary exacerbation. So fast forward a little bit more. So they actually then substituted that corrector, the Lumacaftor for Tezacaftor, and then added the Ivacaftor, which is the potentiator. So this is known as Symdeco. And so this has less side effects for patients, but still the same kind of increases in FV1, about 4%. But it was also shown to actually increase BMI, which Dr. Hornick talked about how it's really important for BMI in our patients, because it's directly correlated to FV1. And then it's shown to decrease exacerbations by about 35% as well. So what is the newest thing on the market? So as you kind of heard, Trikafta is the biggest thing out there. So this was done and studied for patients that only have one copy of FIO8. So then this really expanded access to a lot of patients. And then there's even other mutations that would qualify for this too, but the main one is at least one copy of FIO8. And so what they did is they added two correctors, Alexa Kaftor, Tezkaftor, and then in addition to one potentiator. And so that works very similarly, but now we have really great increases in FV1, about 13.8% on average. I actually had a patient go up more than 30% after starting Trikafta. This reduces exacerbations by about 63%. And currently this is approved for ages six and over. So let's start with some cases. So let's say we have a 20 year old woman who has the mutations for homozygous FIO8. She has very severe lung disease, FV1 at 25%. She has pancreatic insufficiency, really uncontrolled diabetes with the A1C of 14. She also has liver cirrhosis with child puberty, active abscesses, pulmonary infection, chronic rhinocerosis, GERD, and bipolar disorder. Chronic rhinocerosis, GERD, and bipolar disorder. She comes to see you for follow up because like we said in South Texas, these patients live far away and she can't come to see you in the CF clinic. So she goes to the general pulmonologist. Then she's like, well, I've heard a lot about this modulator therapy. So what we talked about, does this patient qualify for CFTR modulators? So yes, because she has qualifying mutations. No, because she has liver cirrhosis. No, because she has uncontrolled diabetes. Or no, because she has an active NTM infection. What do you guys think? So kind of mixed, but actually she does qualify because she has qualifying mutations. And we'll talk about kind of monitoring maybe contraindications or adjustments that you have to do. So when they start on modulators, there is a relative increase in LFTs, especially with Trikafta. So we have to monitor their LFTs every three months during the first year of treatment and then annually thereafter. And then for the pediatric and adolescents, they can have effects of cataracts. So we have to do a baseline and annual eye exam. So for patients with renal disease, which we're gonna start seeing because our patients are getting older, there's no dose adjustments for mild or moderate. But in these studies, they actually didn't study anybody on dialysis or with like severe cirrhosis. And so it's only to be used with caution, but for patients with severe renal impairment or on dialysis. And so I know that some patients we've had at other centers be on modulators for with NCH renal disease and do fine. So for people with hepatic impairment, it really depends on the severity and so which Child-Pugh class they are. So for Child Class A, there's no dose adjustment, which is great. But Class B, you wanna do some dose adjustments, which will be on the kind of package insert with the medications. And then with Class C, it should not be used or used with caution. And these are kind of things that you really wanna talk to patients about for risk and benefits, which can be done with their CF team. But these are things that you can talk to the patients about as well. So what are side effects that happen with these medications? I mean, this list is pretty long. Things that we've seen more heavily would be like headache, which can occur at 17% or so. Some people can get abdominal pain, who we've seen with Trikafta that increases their risk for constipation. We're not sure exactly why, but they're at risk for DIOS. I've seen some patients where I've actually had to take off or modify the modulators because they've had so many admissions for DIOS. Other things would be a rash. These patients will get a rash on their palms and in their arms and legs, but that kind of goes away by itself without any sort of treatment. We talked about the liver dysfunction. They can cause nausea, dizziness. And then the kind of like URI and flu-like symptoms, mostly because these patients then get what we call the purge. When they start these modulators, all their receptors get activated, and then all this mucus comes out of everywhere. And so they confuse that with like, okay, maybe I'm having a sinus infection or something like that. And then we talked about, really importantly, cataracts in adolescents and children. The other thing I wanted to add that was not on this slide is that we've seen actually increases in mental health issues, too, with these medications. So it's really important to then screen these patients, talk about depression and anxiety, which PCPs and pulmonologists, they'll kind of talk about. And we've actually had to take some patients off of modulators because they had a lot of suicidal ideations or had been admitted to the hospital for suicide attempts. So let's do a different case. So we have a 27-year-old patient who is homozygous for F508. They have very mild lung disease. FV1 is actually 92%. They're on Trikafta. They have pancreatic insufficiency and GERD. They're followed in your clinic as the general pulmonologist for an abnormal CT scan with cavitary lesion. You then do a bronchoscopy. The cultures grow aspergillus, and you decide to put them on boriconazole. The other medications this patient is on is on Creon, Simpicort, Albuterol, 3% hypertonic saline, pulmozyme, and pentoprazole. What CF medication do you need to adjust? Okay, would it be A, Trikafta, B, pulmozyme, C, Creon, or none of their medications? Perfect. So actually, it's Trikafta. This talk about modulators wouldn't be complete without talking about the interactions and side effects. So when you're, like let's say you're treating a patient and they need fluconazole for a yeast infection or things like that. So for these CYP3A inhibitors, they really increase exposure to the medication and can cause toxicity. So the dose should really be adjusted for moderate or strong CYP3A inhibitors. Strong ones being like ketoconazole, the other antifungals, hydroconazole, POSA, VORI, clorithro. And so these patients have to be really adjusted or else they can have toxic side effects. The moderate ones would be fluconazole and erythromycin. Then with the CYP3A inducers, this actually decreases exposure and diminishes effectiveness. So co-administration is not recommended. So for patients with NTM or other diseases, you really want to kind of avoid, like either like rifampin or rifabutin and choose other different therapies that would actually not interact with their modulator. And then it's really important too, some like seizure medications, over-the-counter medications like herbal remedies will have a lot of St. John's wort in there. So you really want to warn these patients as well. And then what about COVID therapies? I think this is really important because we see CF patients all over the place and they get COVID, right? They may not be seeing their CF center when they get diagnosed. And so what do you have to do with these medications? So there's no data suggesting interactions with COVID-19 vaccines, even though patients have brought that up, or monoclonal antibodies. But they do have interactions with Paxilvid. So the Paxilvid interactions are pretty strong. And so this is kind of a recommended table of how to adjust that with the different modulators. It's a little bit weird. So I always like email these patients also to tell them, hey, like you don't take any Trikafta except for day one, the orange pills, day five, and then you don't take anything normally until day nine, which is kind of confusing for patients. But it's also really important that if you're diagnosing any patients with COVID and put them on Paxilvid, please call their CF team or tell them to adjust their Trikafta. Hopefully a pharmacy will catch that, but sometimes not, because I've had some patients show up and they're like, oh, no one told me to do anything with my Trikafta. So what about use in pregnancy? So there's actually really limited human data to see if Trikafta can be used in pregnancy, but there's animal data that's showing that it's very safe. The largest study that we've had, they looked at multiple different centers and actually patients who took themselves off of modulators because they were worried about the effects for pregnancy ended up having to restart modulators because either their weight dropped or they had multiple exacerbations, then they had to be back on it. So currently right now modulators are pregnancy class B and the risk and benefits should be assessed individually. So some take home points. We talked about how the CFTR protein is a fancy ion channel, but it has different functions as well. These restore the CFTR protein function. These modulators have been shown to improve lung function, BMI, and reduce pulmonary exacerbations, but they also come with side effects and interact with other medications. Thank you so much. Don't forget to evaluate the session in the app. Thank you.

Cystic fibrosis

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CFTR modulators

mutations

lung function

exacerbations

body mass index

side effects

liver function tests

quality of life

Cystic Fibrosis

CF