Bryan Garcia, MDAssistant Professor MUSC K12 Clinician Scientist Scholar Associate Director Adult Cystic Fibrosis Center Division of Pulmonary and Critical Care Medicine Medical University of South Carolina Charleston, SC Welcome to this Webinar, Siri's today Man. Tuberculosis, micro bacterial lung infections. My name is Brian Garcia. I'm assistant professor at the Medical University of South Carolina. I'm a pulmonary and critical care physician there, and I specialize in taking care of patients with cystic fibrosis. Bronchi, ethicists and non tuberculosis might go bacterial lung infections. So I'm going to take us through a series of cases today with focus on some of the recent uh recently published 2020 American Thoracic Society, Infectious Disease Society and European Respiratory Society. Guidelines on the management of different non tuberculosis mycobacterium lung infections with particular emphasis on mycobacterium avian complex with regards to disclosures, I've received prior honor area from INS Med and I served as a scientific adviser and received received honor area from since Spira. We're gonna go through several cases today. All of them are real cases of patients. I've previously taken care of. All of the patient's case materials has been de identified, and this act activity is for educational purposes Only. Today we're going to review the heterogeneity of potential disease course of non tuberculosis mycobacterium lung infections. We're gonna review some of the potential therapeutic options available for these patients, and we're going to review the recent recent evidence based 2020 guidelines on the management of these patients. Like I said, I've put together a case based format today that I hope you'll find of interest in can relate to. And I'm also going to touch on a few aspects with regards that putting the management of Mac lung infections in context of the current Kogan 19 pandemic that we're all dealing with and working within if you're not aware, here is the 2020 80 s e r S e s C m I. D. And I. D. S. A clinical practice guidelines for the treatment of NTM lung disease. So within might go bacterium. I think it's important to know a little bit of the background of the NTM classifications and there's really four groups of human pathogens as far as I'm concerned, um, and they're based on their microbiological, clinical and epidemiologic characteristics, and I'll tell patients that this type of discussion when I first meet them in the clinic, because for many of them, this is something that they've never heard of, and now they're learning that they in fact are infected by it. And now explain to them the most important micro bacteria on this planet is mycobacterium tuberculosis, for obvious reasons. And most all patients have heard of this, and I explained to them that this is a contagious infection, and that's why it's really the most important, followed by Mycobacterium leprae, which is the positive species for leprosy Again. Now we're starting to be ableto allow the patients to understand where do these infections kind of exist? And then I'll tell them next there's this group of slow growing might go bacterial infections, which includes Mac. And most commonly this is what is infecting them, followed by the rapid growers such as obsesses, Miss Alliances and Valetta. I'll explain to them that these are organisms that are found in our environment in our water supply, and that this is where we come in contact with these organisms. We're seeing increasing evidence of the prevalence and incidents of these organisms as positive. In fact, agents of infection in my clinic and in the United States amongst Michael Bacterial Lung infections, Mac is the predominant pathogen that we're seeing, and I'll explain to patients that there's several risk factors for acquiring this and becoming infected by it. Primarily those air pre existing lung and diseases such as cystic fibrosis, sarcoidosis, Alfa one, COPD and people have had transplants, solid organ or bone marrow transplants, or are immuno suppressed for other reasons. Now explain to them that there's this interesting additional FINA type of patients that we see very commonly and actually makes up about 85% of my patients and that that is thes postmenopausal. White females, who tend to be in their sixties and seventies and eighties, tend to be thinner and tend to be a little bit taller than most other patients. But not always, and overwhelmingly they'll tell me that their heritage is from Northern European ancestry. In particular, many of them will find that they share English and Scottish Irish heritage prior to coming. THIO United States Here is a graphic that takes account patients from the VA from the Veterans Affairs Hospitals and shows how over time we're seeing both increased prevalence and incidents of micro bacterial lung infections, and on the X axis here, you'll see time going back to the year 2000 at the origin and then on the Y access, you'll see the prevalence and incidents rates per 100,000 patients. And you can see that, really, since the year 2000 and 10, we've seen a steady uptick in the identification of these infections in our patients. An interesting piece of the epidemiology that I do share with our patients is that there seems to be a propensity for acquisition of these infections along the coastal portion of the United States and includes, from where we're currently located in Charleston, South Carolina, down across coastal Florida and back up into the Panhandle and the the, uh, eastern portions of Louisiana and into Houston. But it also exists, as you can see it on the Great Lakes and greater prevalence as well as along the western portions in the coastal regions of California. So why, that is is still, to some extent, not well fleshed out, In my opinion of a portion of the reason, certainly, is that in my part of the country, at least we have greater numbers of retirees, and they clearly are at increased risk for acquisition of this infection. And likely that's a primary reason why, at least in the southeastern United States. We see greater amounts of it along the coastal regions. I really make it clear the first time I meet a patient, that there is a broad range in the heterogeneity of the potential disease course that a patient may experience. We're seeing an increased frequency of incidental identification, these air patients, that air coming to me and they're saying, Hey, Doc, um, I'm here because I'm told I have this infection, but I don't have any symptoms. I recently had a coronary CT scan and they saw these little nodule Z's. They said they have tree and buds and then a doctor did a bronchoscopy on me and they said, Now I have something called Mac in me, but I have no symptoms, and I'll explain to these patients that about 30 to 40% of them over the next three years will spontaneously clear these infections and they'll not ever have any symptoms. And the rest of them may in the future, go on to develop, develop symptoms and may require treat. Yeah, another subset of patients come to us and they have symptoms when they come, and they're already coughing or having increased sputum or shortness of breath. They may have fatigue, night sweats, weight loss, um, loss of appetite. Difficulty even asleep. Andi. Other types of be symptoms. They may already have had a CT scan and even had the identification of NTM in Either you know, multiple sputum isolates or on a bronchoscopy bronchus Coptic sample and in these cases will initiate treatment. And again, there's broad heterogeneity in the disease course that these patients will go on to experience. Some of them will achieve micro biologic cure, and they will clinically improve. And this is, of course, our goal for every patient. Some will experience micro biologic here, but despite this, they have now underlying bronchi excesses, and they will experience persistent, perhaps new symptoms or different symptoms after successful eradication of the micro bacterial species. But they still experience symptoms for some patients, despite multiple months and even years of therapy, their symptoms will progress. They will not improve. And they may even experienced worsening radiographic features, uh, including capitation of the lung, and we will add on a multiple new antibiotics, and we refer to these patients as refractory if they're still remain persistent, positive and have active symptoms and then, interestingly, there's a subset of patients whom we treat. We do not cure them from the standpoint of infection, where we cannot say, in fact, your infection is gone. In fact, we may even persistently isolate out mycobacterium from their lung. But yet they clearly respond clinically to the treatment such that after 12 to 18 months of therapy, we actually will give them a break from treatment. And I think this is a very important a topic to present to clinicians. Taking care of mycobacterium is to consider among patients who don't successfully here the infection that they may have actually clinically improved. You may have reduced the burden of infection low enough that their that their immune system is now able to compensate, and they can now essentially live with this infection, at least for some period of time until their symptoms go on. To justify repeat therapy amongst this group of patients, where we achieve cure of the micro bacterial species, some of them will go on to reinfect, and in fact, when you look at patients who have been followed for 10 plus years, you'll continue to see that that they will re in fact and interestingly, in amongst those patients, those female patients I was describing. It seems that they have a propensity for reinfection of micro bacterial species. Do they get Pseudomonas? Yes. Do they get staff? Yes, but they haven't overwhelming propensity for reinfection with micro bacterial species, which to me, really suggests some form of underlying immune system deficiency. And same for this other group who never achieved microbiological here. They still may go on to, of course, reinfect. Perhaps, uh perhaps, uh, in fact, with a different species altogether. Whether I said it's a different mycobacterium going from Mac toe obsesses or perhaps even back to pseudomonas or even co infection. So getting into our cases first and let's begin, we're gonna kind of start with one end of the spectrum of disease. Andi finished with the other end of the spectrum, beginning with the asymptomatic patients. So first here is a patient that came to me 65 year old female, never smoker, and she was recently diagnosed with melanoma. She had a local invasion in her arm, and for that reason she underwent pet imaging. She had no pulmonary symptoms. When she came to me, she was actually very healthy. Loves to play golf and exercises regularly on def. You if you saw her in clinic, you say this is very healthy. 65 year old female and on pet image ing on the C t portion. Uh, sorry. On the pet portion, they saw a lesion in the right upper lobe that was a little bit larger than one centimeter, but it was a solitary lesion. So if we're thinking about melanoma to think it, could this just be a metastatic lesion, solitary lesion to the lung? That really didn't make sense. She underwent bronchoscopy, and our plans were to do a radio abyss, uh, to obtain a sample of that nodule relation on the pet CT. And when we got into the airway, what was striking actually was the significant amount of mucus on DWI suction that mucus. We then, uh, went in with the radio Eva scope, and we were unable to ever identify any sort of modulation that justified a biopsy. We did send this mucus off for cultures, and it came back positive for math. Here is a a portion of her CT scan, and here's that lesion that we saw that prompted us to plan for a biopsy. Here, you can see some very mild practice extra bottom, which is associated with micro bacterial infections in in these, uh, these post menopausal females and, um, some tree and bud changes in this actually fairly significant right middle lobe bronchi ethicists that she had. But despite this, she really had no symptoms. So the question is, should we treat or should we not treat this patient? And the 2020 guidelines really speak to this? What do you need? This hasn't changed. But here's what the guidelines recommend this need to sputum samples taken apart from each other that are both positive for the same might go bacterial species or one bronchus Coptic sample. So in that sense, she checks that off. I mean radiographic evidence of disease. And frequently, if there's capitation, I'll say we will treat these patients even without symptoms, because that's just a sign of more greater disease progression occurring earlier. And then we need to have symptoms that you can't attribute to another cause. So when when when we're talking about pulmonary symptoms, we, as a group agree. We need to make sure that the pulmonary symptoms this person is experiencing. We can't attribute to their c o. P. D. We can't attribute to their cystic fibrosis. We can't attribute to their rocky actresses, so we'll ensure that those other diseases are optimized from a treatment standpoint. And I will say that it's very important to because almost all of these patients are going to have bronchi ethicists. It's very important to have put these patients on some form of early clearance with hyper tonic, saline, albuterol and some form of airway clearance device. Before you say Okay, this these symptoms are due to the Mac or due to the obsesses. The second is if they're having fevers, chills, night sweats, fatigue, weight loss, anorexia These are more difficult symptoms to approach. These are typically seen in those patients who are in their seventies and eighties and and very well may have other reasons. Toe have these symptoms, and you've got to really weed out, Um, and make sure that there's no other attributable calls for these symptoms. So in our patient she was asymptomatic, and we've monitored her off treatment. I put her on airway clearance alone, and she's done great, and she has more than three years of follow up, she actually remains persistently positive. Her image ing looks essentially stable, neither better nor worse. And she's never developed significant symptoms that justified therapy. So moving on to our next case. And as we're moving kind of across the disease spectrum here, here's another 65 year old female, and she was a heavy smoker. She was a 45 pack year smoker, and she still smokes about five cigarettes daily, and she came to us because she had increased cough. Suddenly it is unusual increase in sputum production, and she has been hospitalized several times in the past year for what they called COPD exacerbations. She gets antibiotics, different types of antibiotics, and she experiences clinical improvement. But shortly after coming off of the antibiotics, her symptoms recur, and now she has had multiple speed. Um, there's group, uh, mycobacterium ADM into salary over this period of time. So here you can see these kind of ground last modularity. Is that air peripheral based? And the reason I show this is really that radiographic features of mycobacterium are broad. Uh, tree and bud changes are common. Novels are common bronchi. Ethicist is common, but we may see consolidations, we may see ground glass capacities we may see, um, capitation. And so there is a lot of different radiographic features that one might attribute to might go bacterial infections. So should we treat this patient? She has two plus cultures. The same I feel bacteria Bislett taken temporally apart, she has radiographic evidence of micro bacterial infection. And then the question this is this is the important question for this case. Are her symptoms driven by COPD emphysema? Or is there a component of mycobacterium going on here? And my opinion? Waas We looked through her stuff. She's already on all the right inhale therapies. Um, she needs to quit smoking that that is paramount. She's going to have a bad outcome without quitting smoking, both with regards to her, um COPD as well as her micro bacterial infection. But other than that, I felt that she was really optimized from a therapeutic standpoint, and it was in particular that unusual response that she has to antibiotics. The antibiotics stop, and shortly thereafter, her symptoms rebound. And that clued me in. She wasn't growing pseudomonas. She wasn't going other Michael bacterial infections that clued me in that I felt that there was sufficient evidence to suggest that there was a that MTM was at play here because she had been on a zip through my since so many times during the lead up to meeting May. We sent her isil it for drug sensitivity, texting. And this is part of the 2020 guidelines that when you identified back and you feel that this needs to be treated, you need to send it for drug sensitivity testing and the key drug for Mac that you need to know. Is it sensitive For in particular is as if the mice and you need to know about the macro life sensitivity that's really your backbone of treatment. And in this case, I started this patient on Thrice Weekly, a zip promising right champion, and Nathaniel tall while we waited the drug sensitivity testing. So this comes back to our 2020 guidelines, um, in which a series of questions were asked by these experts, and they provided their recommendations, their consensus recommendations as well as their, um, the strength by which their recommendation they made plus. And so in this scenario, we describe a patient with mackerel. It's susceptible from Mac. And the question is, should we go three times a week? Treatment? Um, keep him on This is macro light sensitive. So we go three times a week treatment or should be used daily. And the experts in this scenario suggests if the patient meets certain criteria, if it's non cava terry disease in its macro light susceptible and this is new treatment, this is a person who is naive to therapy. The guidelines suggest a thrice weekly approach. Um, this is a conditional recommendation. This is actually, uh, being studied at the moment. And they have very low certainty in the estimate of the effect of that recommendation, however, that for non capital so for patients with kava terry disease or severe advanced modular bronchial chronic disease, uh, they do recommend daily treatment rather than three times a week treatment. Um, why is this why? Why is it that sometimes we say daily and it might be better? Or why is it that thrice weekly might be better? The rationale for the thrice weekly in the patients with macro light, susceptible non capital Terry disease is that it's likely that they're more likely to tolerate their therapy and therefore have, uh, increased likelihood of completing this prolonged course. And given the fact that we know sputum culture conversion is a similar in these two groups. Well, exposure toe less side effects related to the meds. Increasing compliance is likely beneficial. So once the decision is made to treat, our group suggests this continuing to monitor sputum monthly for to see when is it that we achieve culture conversion. And I wanted to talk just for a moment now about how it has our practice changed as a result of the Koven pandemic. Um and e would suggest that really, the practice of medicine for one has transitioned Teoh a greater utilization of telemedicine, which is great for patients who are looking to come to someone like us at university centers where they may live far distances away from us. As Pullman pulmonologist with expertise in these infections, especially considering that we take care of an elderly population, it's more difficult for them to travel and they have concerns about the potential exposure to co vid in the waiting rooms, for example. So this has, um, this is, I think, really change the approach to delivering care The other aspect of care that's changed significantly is, um, that we now in the midst of these 12 months of therapy, remember, we still need to be checking labs. We still need to be checking monitoring for drug related toxicities, including getting EKGs to monitor few TCS getting audio logic examinations. And so this is put a significant burden on our nursing staff who now these air not being done in house, so to speak, and instead that being done in the community. And we're really relying heavily on our nursing staff and coordinators. Thio coordinate with patients to get these done, um, on the appropriate timeframe, many hundreds of miles away, and then to coordinate getting bad information back to us so that we can ensure that we're still delivering high quality care. Um, one recommendation that, um, I would, from a swell from these guidelines is when you have decided to treat patients on bets, say, for example, you're gonna treat them with the conventional. Is that for myself, my family, my family's all up front? I really recommend a staggered approach to treating them. So let's start with Is it for my son for a week the next Monday ad right champion and the following Monday, thereafter. Addy can be tall that way. If a patient experiences some sort of side effect early on, you can kind of pinpoint which drug is. That's likely contributing to that. So what about treatment? Duration? Um, this comes back to our guidelines and patients with mackerel. It's susceptible Mac to patients be treated with less than 12 months after culture negativity or greater than 12 months. And the guidelines suggest that they should receive treatment for at least 12 months after culture conversion again, a conditional recommendation in the experts agree that they even have very those certainty Aziz to the effect of this recommendation. So are our next case, as we kind of move along the disease course from asymptomatic, and eventually we'll get to refractory disease. Eso we describe a 64 year old female here. She's previously healthy. She never smoked, and she came to the ER with sudden acute onset of him. Ahth assis Andi. She says that she coughed up about five tablespoons of blood over six hours and and this is very worrisome to her. Um, she had actually no other prior pulmonary symptoms leading up to this on this one evening and she had no be symptoms, and she comes to the ER. She started empirically on brown spectrum antibiotics. Her hypothesis resolves over the following 24 hours she gets sputum cultures taken while she's in the hospital. And then, about 2 to 3 weeks later, they come back positive for Mac multiple sputum cultures. Here's what her C T looks like, and what you'll notice, obviously is. The right lung looks pretty healthy, but the left lung has this approximately 2.5 centimeter area of capitation, really in the middle of the lung, with some areas of relatively thick walls around it, as well as Cem proximal modularity ease. Here's some additional cuts taken further down her loan, and again, I want to just draw your attention. You can really start to see that the this practice extra bottom also exists on a bit of a spectrum here. It's more pronounced in our private patient. So what about the treatment of cava Terry disease? We talked about, you know, macro light, susceptible non cava terry disease. But what about the treatment of cava Terry disease? We know that treatment outcomes are worse in patients with fiber cava, terry disease. And so our recommendations for this are presuming this is Mac, of course, up from a r e therapy. Is it to read camp anything and it'll This should be daily. Although I still recommend staggering it over three weeks. But it will be daily because we no longer meet those, uh, macro like susceptible non cava, Terry. Uh, description. So in this case there, in this scenario, we're gonna go a daily A R e, and upfront, we're gonna add Ivy, Emma Cason, and the goal is somewhere between eight and 16 weeks, depending on patient, tolerable ity on bond. I always tell patients, Let's have a goal for 12 weeks and we might extend it, but if it's not working out, we might shorten it. It's really important to share in the management of these patients with pharmacists who has some expertise and managing. I mean, like the sides and in a case in as well as right fam pin and knowing the drug drug interactions these patients are gonna have many of them are elderly. Many of them are on Synthroid. Many of them are on Coumadin and are going to need a dose. Adjustments Andi also as well as to help with the monitoring of potential drug toxicities and kidney dysfunction. In, um, certain scenarios. I will recommend surgical reception for these patients, but that is taken. It is not taken lightly. And we need to really share in discussion with patients about the pros and cons of that. Um, really, it needs to be otherwise very healthy patient with very localized area of capitation who is very highly compliant to therapy and likely to have a better treatment outcome if we remove this one area that appears to be, um, basically incurable, without without reception. Yeah, so going back to our guidelines. Should patients with Mac pulmonary disease be treated with parental and moccasin or a structure Meyssan containing regimen or without a parental amicus in, or streptomycin containing regimen? And so the suggestions are that for patients with kava Terry, um, or macro like resistant man Yes, up front, they should receive intravenous M casing. Andi, this is a conditional recommendation, a moderate certainty in the estimates of their effect. Um, we need to keep in mind on guesses what the experts said when they were these guidelines. We need to keep in mind that there are few options for intensifying Orel therapy, Um, particularly, um, in patients with evidence of a more progressive form of disease capitation or in patients who have upfront mackerel. I'd resistant therapy. These people have fewer options. And so the the expert committee said that in their opinion, for these reasons, the benefits of intravenous therapy upfront really outweighed any of the potential risks and in particular, the benefits. When delivered appropriately with good quality toxicity monitoring outweighs the potential risks. So, like I said, you know, AM occasion is associated with significant side effects. We do closely monitor their kidney function upfront and then every, uh, few days for the first week or two, and then we space that out Thio. Every every couple of weeks, we'll check it. Um oh, toxicity is common, and we do get ideological. Sam's every month for these patients, and the stabler dysfunction is common. Vertigo type symptoms is common, and many of our patients do see physical therapy. Thio kind of learn some certain maneuvers to try to help with that, so our next case is a 49 year old female, very nice lady. She's never smoked. And at a very young age, she was diagnosed with with Michael Bacterial infection of the Lung with Mac, and she has just been dealing with this for several years now. Before she even came to see us. Um, she said that you know, she she has little insight into the severity of her illness on Bond says, You know, I've just been on antibiotics for on and off for about four or five years now, and I wasn't sure if she ever achieved culture Conversion. Didn't sound like it from the description, that's for sure. And she says that leading up to coming to see us, she's just really feeling terrible. She's got more coughs. She's got more shortness of breath. She's suddenly just dropping weight unexpectedly, having fevers at night, night sweats, um, complete loss of appetite. But interestingly, she still had this really wonderful lung function. She still had a nephew be one of 99%. She had no obstruction on her PFCs when she came and saw us. And this is what her c t look like. I mean, she has got these three and blood changes on the right here and then with bronchi ethicists and then, obviously on the left. You can't feel to miss that. She has this very, very thick walled area of capitation in the left lung with volume loss. I mean, if you compare the the two lungs, you can see their significant volume loss of hearing there on the left on DSO, we took her cultures, we sent them off, and unfortunately, she was resistant to macro lines on DSO. You know, she's got capitation and she's got mackerel. I'd resistance. And so we have access to this. This antibiotic called Cliff as a mean that you may have heard of on DSO. We gave her upfront intravenous and McKay, since she had never been on intravenous therapy before. Right, Pham Peanut and metal and cloth Azemi. And so if you haven't heard of cope as mean, or if you have less experience with fast, I mean, it's been around a long time. It's been historically used for the treatment of leprosy. It's not commercially available, it's a FINA zing die, and it acts basically by binding the guanine bases of bacterial DNA, and then it impairs their ability uh, to proliferate. As a result, the most common side effect that you will definitively see if you ever see a patient that's on low thousands is they really begin. Thio take on this orange hue, their skin takes on orange hue and and they really secrete it through their sweat. I've actually had patients who were on Cliff as, um, ing for pulmonary infections, who needed me replacements, and I literally had the orthopedic surgeon called me from the operating room and say, This woman's knee Her bone is orange, her bone is literally orange. Andi was wondering if that might have to do therapies that we were giving. I said, Yes, it ISS Patients will say that if this color is their teeth and that they need toe bleach, their teeth and that even their bed sheets if they have white bedsheet speaking to take on this orange Q. It takes some time to get to a efficacious level. But once there it's. The drug is relatively well tolerated, and it will stay there for quite sometimes is essential along mhm. Uh um for patients like like this lady, we need to, you know, think about where we gonna go with her. She's mackerel I resistant. And she's gonna need to come off of the intravenous indication on DSHEA. She is likely going to need a very aggressive regimen for a prolonged period of time, given Thea underlying disease severity that she had mhm and eso. In this scenario, you know, she achieves some improvement clinically. But after stopping the in the case and some of that what that clinical improvement that we saw began to get lost, and she began to have recurrence of those symptoms That really bothered her up front. And like I said, you kind of knew going into this that she was gonna need something else. She didn't clear her cultures despite that aggressive therapy. And so we added on inhale like his own in case in for her. Um, and several months later, fortunately, we see, actually that she did go on to achieve culture conversion after the addition of that Andi, this has been studied. Now inhale the light visible indication for for this type of patient, someone who's been on therapy for many, many months, uh, in particular. The study looked at six months of therapy. Andi, Then the addition of like Xoma am a case in this scenario in increase the likelihood of achieving culture conversion for these patients by about 25 to 27% over standard of care. Andi. That's really a tremendous achievement if we can cure these infections for these patients. Um, so again, here, here's those guidelines that came out this year just to draw your attention to them. I highly suggest taking look at them if you have a chance. Um, and what they do suggest is in particular for there's not too much yeah, therapeutic specific suggestions, with the exception of the ones we discussed in in particular for patients with, um, refractory infections to really go and try to obtain this inhaled solution for your patients because of the increased likelihood that they're going to go on to achieve a culture conversion. Um, and and quite frankly, we don't have the same level of evidence for this type of suggestion for for the remainder of the guidelines. So going back Thio Ah, six In the guidelines, those in patients with mackerel I've susceptible Matt Palmer disease should a regiment with inhale indication or a regiment with inhale without inhale education be used for treatment. Um, and so what they suggested was that in patients with newly diagnosed Mac pulmonary disease, newly diagnosed, neither ivy nor inhaled. Uh, sorry. Neither, uh, inhale them a case in which can be delivered as a parental formulation, nor the inhale like Izumo indication was suggested. But that is based on the current knowledge. And therefore the recommendation was conditional, and they have very low certainty in the estimate of the effect of this recommendation. And it's very possible, in fact, that in the future we may see this recommendation change such that inhale therapy is recommended is part of the upfront treatment but impatient to have failed therapy after at least six months of treatment. The recommendation is for the addition of liposomes inhaled, I presume Lima case in solution to the treatment versus continuing the standard Orel Regiment only. And this is one of the few recommendations in the guidelines that the experts say this is actually a strong recommendation on that speaks to the fact that this is one of the few guidelines that truly has a multi center, randomized, blinded control study upon which they're able to make this recommendation on dso that speaks to, um, why they made this. This is a strong recommendation. So once you make a decision or the suggestion to your patient, we should add, um, the inhaled in a case like someone in a case in, um, what can we do to really optimize the like? Because they're gonna take that and be able to tolerate it? Well, So first, let's just hung about the oral medicines. They are commonly associated with side effects, bad taste in the mouth, saltiness, nausea, just abdominal cramps. And so I will suggest to them, Try taking medicines at bedtime and take them with some Zafran and maybe when the medicines or perhaps at their greatest concentrations, maybe you'll be asleep for that. And hopefully it will affect your appetite less. And if you identify that, one anti microbial in particular is causing symptoms that are particularly bothersome and these air patients are on daily therapies, I might take a more personalized approach to care and say, Why don't we take that right, Pham Phan and do it Monday, Wednesday, Friday. But continue your other antibiotics daily. Or if we think it's the economy talk, you know, let's take that down to Monday, Wednesday. Friday. Um, keeping in mind that you know, ultimately, if we can't get the patient to even take the drug because they have so much side effects, then that drug is no longer useful. And so now, talking about the inhaled like those, um, I'm a case in the most common side effects I think that you'll experience with your patients are likely to be hoarseness, cough and chest tightness. Some patients will have all three. Some will have one or the other or two. But overwhelmingly, when you take care, a lot of patients are with NTM infections, and you use this therapy a lot. You do notice that patients will experience these symptoms. And so I've taken a couple of approaches. Thio. Really? How can I still get them to take these this therapy, because of the downstream efficacy that I want them to achieve One approach I'll take is I'll say, Well, does it seem like it's at the end of your nebula ization that it's most bothersome? Because if so, then maybe we should need to cut your nebula ization down to a half of a dose and see if I could just get that half dose in them at least every day. Um, if they say it seems like it, it built up like at first I tolerated it. But then after a while it seemed like I didn't tolerate anymore. This to me suggests that like those frequency is too great. And I'll say, Why don't we take it down? Let's try it. Maybe Monday, Wednesday, Friday. Let's try it every other day, you know, again taking a personalized approach to their care and saying, You know, maybe on Tuesdays and Thursdays you have. Do you wanna, you know, play bridge with your friends? Then Monday, Wednesday, Friday, Let's try and take that medicine and give you Tuesday Thursday off. So I guess what I'm trying to say is, if it seems like it's the amount of treatment at one sitting, I kind of deescalate the total dosage for that day. Whereas if it seems like the symptoms built up over time, I'll decrease the dose frequency, Andi. Then I'll tell them afterwards. You know, at some point maybe we'll try to get you back up to full dose daily, and so patients have access to communicate with me through their chart and and they'll let me know how things are going well, things are not going well and then we'll make adjustments. And it's really a partnership in this treatment of this disease on DSO. When we go back up on DWI, read up titrate therapy again, we're It's a very much a personal and individualized approach to managing these patients. Where you kind of say, what was the upfront issue? How are you doing now? And do you think you're ready to begin to go back up? And is it? We're gonna just go to 45 and six days a week over the next three weeks? Or are we going to go to three quarters of the treatment and then maybe the full dose again? Um, one thing I I've done anecdotally, I don't know how much benefit it really provides is I will have patients take out Butera lift chest tightness is a major symptom for them on DSO. Sometimes that does seem to help us well, and then lastly, you know, I always try to optimize the management of their underlying bronchi. ECT assists when we're taking care of these patients and and part of that is going to include hyper tonic saline, and I do think that there may be an additive kind of airway. Um, um, just that they're airways become particularly bothered by all these inhale therapies when you're adding on so many. And if we're treating Mac and we know that we have such good evidence to support the use of life is normal. And the case in these patients less evidence to support the use of hyper tonic sailing. We know that hyper tonic sailing is very irritating to the airway. I'll say, Why don't we? Why don't we take a break from the hyper tonic saline? And and let's try to get the anti microbial in you because I think, likely that z going to provide greater clinical benefit then the hyper tonic. Same thing does. So you know, in summary. Um, I'll just say we talked a little bit about the epidemiology and TM and and Mac lung diseases. Not rare. It's probably poorly recognized, but it's improving. Um, it's improving because radiologists are doing a really great job of saying that there see these tree and bud changes and consider atypical infections, including on tuberculosis might go bacteria in their reports and the culture methods are improving as well. The treatment of MPM is complicated and drug toxicities drug drug interactions is common. And we need to share this information with patients upfront and let them know that we need that. We're gonna take a, you know, attempt to take as individualized and personalized approach to taking care of them as possible. Going back to one of those earlier slides I do always upfront share with the patients. Here is the spectrum of disease. Where do you fall right now? Maybe I can provide that information. But where will you end up? Is gonna be difficult to predict, Um, and the treatment of it. Like I said, it is fraught with a lot of the side effects and potential toxicities. And so we're gonna need toe way the severity of your symptoms with the different treatment options along the way. And this may be really a chronic disease that you live with for many, many years on DSO. That's why we need to take this personalized approach, Onda. Lastly, we really need more research in this disease. We need to understand Why is it that these specific individuals are at such increased risk for acquiring it, becoming infected by it on we need additional new therapeutics. We finally have one well studied therapeutic. But we need mawr because there it's just to such a great burden of disease now in in the society. And we need thio invest more in, uh, in understanding this infection in treating it. So I hope you found this webinar in educational, and I hope it may help provide insight into how to take care of these patients. That air so complicated. You can watch this again if you'd like, and you can find it here on the I Q and A website. A swell as, um, see additional. Um, there's additional experts in the field who have some of their recommendations featured. Um, and, uh, in particular, there's gonna be access to, um, several different physicians and experts with regards to frequently asked questions pertaining to the management of Mac lung disease, and you can see how they might recommend addressing these questions again. My name is Brian Garcia, and thank you very much for joining us today.