Chapters Transcript Case 2: Diagnosis and Treatment of MAC Pulmonary Disease and Surgical Options for NTM Pulmonary Disease Course: Bronchiectasis and Non-Tuberculous Mycobacteria Case-Based Symposium: Everything Clinicians Need to Know Thank you all of you for joining us for this uh case on uh Mac pulmonary disease, uh, that I'm going to be presenting now. OK, here are my conflicts of interest slide just from clinical research trials that I'm doing. All right, so we know that, uh, NTM is everywhere. I was lucky enough to be asked to give a talk at the APSR on environmental aspects of NTM thanks to Doctor Kamelhar. He helped me out with that talk, um, but it's ubiquitous everywhere in lakes, rivers, it really likes fresh water, not salt water. Uh, we see it in the municipal water systems, pretty much everywhere, plumbing. Uh, is perfect for it. Uh, it developed, uh, it, it likes to live on the biofilms that form in a lot of our shower heads and our, uh, sinks. Uh, we know it gets aerosolized, uh, in very warm, steamy conditions like hot tubs, steam rooms, indoor swimming pools, uh, and it can, um. Live very well because of a lipid rich outer membrane that allows this hydrophilic impermeable barrier to an uh antibiotics and disinfectants we've learned that it is resistant to high temperature states and we've also started to see cases where desiccation tolerance means it can uh remain on coins and other um objects, uh, even without water being present, so it's pretty much everywhere we've got it all over us right now as we're speaking. Um, we know that, uh, there are slow growers. We're gonna talk about MAC today, but M. Concesi and M. Zenope are in that group, and there's also rapid growers and Doctor Casper Bauer is gonna talk a little bit about Msesis, but the species and numbers are actually now over 200 and growing each day. Within MAC Mycobacterium AM complex, there are 12 species. The ones that your lab will report most commonly are Mycobacterium avium, intracellulai, and chimera. Uh, many labs just report out Mycobacterium avium complex because they are not doing the subspeciation. So in the guidelines that were published in 2007 and also the most recent ones from 2020, we know that to make a diagnosis of NTM pulmonary disease, you must have symptoms and we'll talk a little bit more why that can sometimes be problematic nodular or cavitary uh opacity, so have to have something radiologic going on that's consistent. And then you must uh make a microbiologic diagnosis. Either two separate sputum cultures that are positive for the same organism, one bronchoscopy, uh wash or lavage that's positive, or transbronchial biopsy that ends up by or a transthoracic that ends up growing uh NTM species. And um you know as we talk about uh how do you address uh we'll do a case of, you know, what should you do with a patient that you first meet? How do we know? are they gonna be the patient who's gonna progress? Are they gonna be the patient who's gonna stay stable for 20 years? It's often very difficult to tell that on day one of a patient presenting, particularly with an abnormal CAT scan with bronchiectasis to figure out what subgroup they're gonna fall in. So I highlight these two studies which show that if the point is to look at the patients that were stable. So in this first study 23% of the patients were stable and of those, half of them spontaneously converted sputums without treatment in this group, uh, they looked at the patients that did not end up getting treated, um, uh, the more, um. Mild patients and again half of those patients end up ended up converting their sputum so not everybody who initially presents with diagnosis of multiple cultures positive will stay positive. However, there is a large majority. The other 30, the other 75% or three quarters that will remain positive and many of those that will progress and that's one of the reasons why the newest guidelines that came out actually um actually advocate treating in most cases so but that is often a hard decision for the clinician to make. I want to point this out as well, and I thank Doctor Daly for putting together um this slide. Um, the, um, majority of patients with nodular non-cavitary Mac disease, which is this group here, they, the majority culture convert. I would say um some of the other studies are in the 70s, but 75 to 80% of those patients will will culture convert, and that's what we're gonna talk about in this case. We know patients with cavitary disease, we know patients with macroli resistant disease and obsesses have far lower rates, but I want any of the patients who might be listening today or hear this, uh, broadcast that for many patients we are able to treat them and convert them. Uh, we won't talk about relapses and reinfections down the road, but they can get through therapy often fairly well, but we're left with a quarter or 3% of patients that then are much more difficult to treat, and I think those are the patients that take up most of the time, uh, uh, for us clinicians. So, and that's gonna be uh a case that we're gonna present right now. So this patient presented in 2014, a 65 year old female with a history of scoliosis. We know thoracic abnormalities are very high in patients with underlying NTM bronchiectasis, osteoporosis, GERD, and had a history of pneumonia that year. She presented to her pulmonologist, uh, because she had a persistent abnormal chest X-ray or was referred to a pulmonologist. So she's different than many of the patients uh that are in a lot of the clinical trials because she was asymptomatic. She denied cough, sputum production, hammoticness, dysmnea, night sweats, fatigue, or weight loss. Other than the pneumonia, after the pneumonia was over, she was back to her asymptomatic baseline. So classically, she would not have qualified to have diagnosis of an NTM infection based on the guidelines because she had no clinical symptoms. Her family history and environmental exposure history were negative. She didn't garden, swim, use hot tubs or steam rooms. She was a legal clerk and never smoker. Due to persistent abnormality on her chest X-ray, she had a CAT scan done, and we find, you know, um, out in the community a much lower incidence of CAT scans being done and the diagnosis of bronchiectasis is often unable to be made on a chest X-ray. Hers revealed significant bronchiectasis in the lingula. I'll show you some images shortly. She had an initial workup including a CBC, CMP, CRP, immunoglobulins, alpha one, which were all within normal. Uh, she had induced sputums. They were all negative, so she was able to bring up some sputum while she was induced. She did undergo a full swallow evaluation, including a GI evaluation with manometry. Uh, both were normal. Her pulmonary function studies were normal, and she was started on airway clearance at that time. In 2016, she returned, had multiple induced sputums, and now they revealed smear positive mac. And given that the CT report in 2016 was reported as stable and the patient was asymptomatic, she was clinically followed and no additional treatments were started. So how do you decide who to treat, who not to treat? Some reasons here to watch a patient if they're asymptomatic, if they have a stable CT, stable pulmonary functions, a less virulent species, low burden of disease, and minimal comorbidities, safe to watch, follow up in 6 months, as long as you're following these patients closely, safe to watch a number of them. Who should you think about treating sooner? Those with significant symptoms, progression on CT cafeter disease, declining pulmonary function, more virulent species, smear positivity. And comorbidities. We know that low BMI, immunosuppression, underlying lung disease, and malnutrition are all going to be risk factors for progression. So sometimes though, your patients will have Items in each column and then you're not sure like this patient who now had moderate smear positivity and what was thought to be a relatively stable CAT scan. So I've asked the panel, what do you weigh as the most important thing when you're trying to decide who to treat and who not to treat. We can start with Doctor Kamelhar. Thank you. So I think most people who know me, uh, in this institution, or many people know me that I kind of err on I I err on the side of, of watching rather than treating. I'm a big watcher. Uh, I think anybody who deserves a chance, uh, to respond to conservative therapy, meaning airway clearance, um, it's already been mentioned that she had her swallow studies. I'm a big swallow study believer, and sinus and reflux and so on. Uh, so if these things could be corrected, uh, and the patient is not clinically, uh, in an urgent state, which this patient was not, um, I'd like to watch and see. So this patient's features to me, highly localized and the lingula, which is a little bit quirky. Um, the fact that she turned from smear negative to all smear moderate smear positive. So in terms of smear positive, that's not an all or none, uh, but moderate smear positive on all three, I think is, uh, is compelling. Um, uh, and, um, uh, as I said, it's, it's a little bit tougher than, than a yes or no. Uh, so the, the guidelines are guidelines, they're not rules. Um, I'd like to see how she does with airway clearance, give her a good try at it, uh, because since there aren't any other, uh, any other things to consider, uh, we'll see down the road the consideration about the surgery because it is so localized. Um, but, but I feel a little bit more edgy than I often do, uh, because of her multiple smear, moderate smear positives, uh, and the fact that maybe that's a signal that things are moving quicker rather than slower. Uh, so, you know, I, as I said, bottom line, I'd give her 3 months of, of aggressive airway clearance, see what I could accomplish. Uh, and then, and then, uh, be, you know, close to the edge of, uh, of treating possibly with the eye of er and, you know, with an eye on surgery in the future. Anyone wanna add anything? Good, uh, uh, I would just say from my perspective the, the, the easiest go no go treat is cavitation. So if I see cavitation for me, that is we're gonna treat, uh, if there's no cafeteria disease and we go back and look at these other issues, some things that weren't brought up here were elevated inflammatory disease. I don't know if they had an elevated CRP or sed rate, uh, anemia, low albumin. These are all risk factors associated with progressive Mac disease, uh, so those are things I would also consider. Uh, but ultimately, uh, this is a slowly progressive disease, and we have time to make the right decision, um, and, uh, and, and we typically do not rush into treatment and so we, we do a lot more watching and people might, uh, think we would do it national Jewish, uh, with those, uh, those caveats of the things that would really drive me forward would be radiographic progression and cavitation. Yeah, I mean, the other thing I'd add to for Mark is just the other no go go that's easiest symptoms, right? I mean, if they feel if the patient feels sick. You treat them because you wanna make them feel better. Now, this woman, I guess, has no symptoms, so she's different, but in terms of cavity, wrist fractures of progression and symptoms, I mean, those are all kind of triggers to to initiate therapy, I think. And I, I think you'll see that's one of the issues in this case is that she was so asymptomatic that it was even hard to convince her to have any treatment when we thought that was necessary. So in Martin. One factor that never gets on these lists of who to treat or not is age, and I can't be the only one that if it's an 83 year old woman, maybe with some comorbidities, who's doing well and thinking, you know what, something else may get her before her Mac doesn't. There's, there's absolutely no reason to treat at this point, whereas a 55 year old with the same symptom complex and presentation, you're more worried about, how does that enter into You guys thinking. Yeah, I, I mean, I totally agree. I, I mean, obviously this isn't, I always tell my patients this is kind of an art form. It's a very patient-centered, uh, decision making process that you try to help the patient decide what they want to do. Um, now, obviously, it's not always clear, and there's no right answer, but I mean, a lot of those, what's your scan look like? What's the age, what's the symptom complex? Are they gonna be someone who can take 3 different antibiotics for a long time, or can they swallow pills? I mean, there's lots of things that go into that decision. I, I agree, I think age is important. Yes, and I agree. The younger Mark, they are, the more aggressive I will be and try and eradicate it or cure them, uh, if they're in their 80s and we have many, we may go with a much more modest regimen. Get check, yeah, just quick, uh, Mark, there are two issues though that relate to age. One is, is it a risk factor for progression? Um, and the answer is in, uh, all studies except for one increasing age was associated with progression and one study from Korea, lower age was associated with progression. So even that's a little confusing. And then the second uh which you brought up, which is tolerance of drugs that decreases with age. So it age has different uh elements to this decision to go or not go with treatment, but it is something to consider. I, I think that it's it's just important to emphasize this patient, the watchful waiting, that this is a watching, not waiting patient, um, because she is, she is progressing in some way, even though she's not ill. That's the important point is watching even if you're not treating. So she developed a second pneumonia in 2017 and then sought a consultation here at NYU um and came in, um, we, we, there were a lot of CAT scans between 2014 and 2018, so I'm just showing you a sample. But they actually had been slowly progressing over the years and when you only compare a CAT scan to the one prior at 6 months, which often happens in busy radiology departments, you may not see change. So very important to look at your oldest CAT scan and your most recent one, and that's where you'll pick up change. So it's quite obvious obvious here that you can see the progression of disease in her lingula. Um, again, another cut showing progressive disease in the lingula. OK. And she didn't have disease elsewhere uh in the lungs in 2018. So by that point she had developed a very mild cough with some mild sputum. It really was not bothering her. She was started on aggressive airway clearance with an exercise regimen because she was playing tennis a few times a week. We coupled that with hypertonic saline and an aerobica, um, but she had really been noncompliant. Um, sputum continued to be smear positive and culture positive for MAC. Um, and so the plan was to begin guideline-based therapy, uh, intermittently 3 times a week. And Anne already pointed out the importance of airway clearance and really, really important to be able to educate patients and use a variety of uh ways to do clearance cause not one size fits all. So just to review the most basics of basics, uh, the dosing of what she was started on was azithromycin. We know that is preferred above chlorythromycin in the new guidelines based on, uh, ability to tolerate once daily dosingambuto is 25 mg per kilogram when you do it 3 times a week, and then she was put on rifampin at 600 mg once daily, um, and that does get reduced to 450 if you have, uh, a BMI um. Uh, if you're less than 50 kg, so she was put on 3 days per week. There is a separate dosing regimen for cavitary disease. Cavitary disease really should be daily therapy, and the etambutole and zithromycin doses are changed in the daily regimen. Azithro is 250 a day. In that regimen ethabuto is 15 mg per kilogram, and often in those patients we will be using IV Amicain 3 times a week. And the new guidelines, uh, advocate when she was first seen in 2014 and 2018, she did not have routine uh sensitivity testing done on her isolate. It did get sent in late 2018. Uh, and so the new guidelines recommend antimicrobial susceptibility testing for ammicain and the macrolide in patients with Mac disease up front, uh, so you can see that she was Amicain sensitive with an MIC of 16, and chlorithromycin MIC was 8 also sensitive. Uh, important to know that many labs will also result habuol, Rifampin, um, aquinolone, unusually all resistant. None of that data is applicable to your patient. The in vitro to in vivo correlation, uh, does not exist except for the macrolides and ammocain. So I wish that labs didn't report those other results, uh, because many times we'll get patients where a community practitioner will have stopped the habitol or have stopped the Rifampin based on sensitivity panels that they have received which says that they're resistant. To OK, so back to the case. So she was started on azithroathambuto and rifampin 3 times a week. We phase them in one at a time, usually a few days on each drug just to make sure of for GI tolerance or rash. She also was referred for thoracic surgery at that time just so she could meet the surge. And talk about risks and benefits because this was localized disease and we really do think about resection up front localized disease with smear positivity. I don't know how she's gonna do. Let's just at least think about surgery as part of the regimen once we get her control after one month of therapy, she developed tingling and numbness in both hands and also felt like she was having some visual changes. So we stopped all meds thinking there was was related to the eambuto. She ended up um having a workup. So at this point, uh, let's suppose she had severe GI intolerance to the rifampin and she couldn't take the eambutol because of some ocular toxicity. What do you like to pair your azithromycin with from our other alternatives for an initial treatment of a patient we'll get to recalcitrant patients in a, in a bit because we know that we have one medication out there that's uh good for FDA approved for uh recalcitrant patients. So Chuck, do you wanna take this one on? What would you pair her to if you couldn't use the Abitol and rifampin? Um, well, yeah, I would say we don't have great substitutes for habuol. Uh, I feel like we do for lofampin and that would be clofazamine. I think there's evidence to support that. Um, uh, we typically would use clofazamine as a substitute, and, uh, but I don't think there's a single drug now that is equivalent to, to uh thambualba, uh, particularly in the setting of, uh, or this concept of preventing infection of, of resistance. So, uh, uh, often I will give clofazamine and start inhale themcain. In this setting, um, um, bedaquiline, don't use a lot of bedaquiline, don't use a lot of linezolid. So those are, I think, easier for me to get and there's good activity in the lab and patients generally tolerate them pretty well. Agree. I mean, I agree. I think if I could get it approved, I'd I'd start lepisomal. Yes, so we probably would try and get liposomal lamicain, uh, our case, often it will not be approved if the patient has not had recalcitrant disease already, and we can use an intravenous form of inhaled Amicain as Doctor Daly said, so that might be an option if we would have, would have needed to uh go a route where we couldn't use the Thebitol or rifampin. Uh, the other, the other thing which, uh, sometimes if you just have GI upset from rifampin you may not have it from rirobutin. You might change the dosing to the evenings before they go to bed. I mean, there's other things the whole panel, I know they do all of these tricks, uh, to see, uh, if you can rechalenge the patient to try and get them on what we recommend as the best regimen. So, um, the other question I wanted to bring up the panel, um, what about just two drugs versus 3 drugs? Uh, what about azithro and ahabuto? And then I'll ask you, what about just azithro and clofazamine or azithro and inhaled Amicain? What about we get asked quite frequently, can't I just go on 2 drugs instead of 3? Who wants to take that one? I, I'll take it just because, you know, we have the study, which a lot of you guys are helping with, so thank you. Um, we don't know the results yet, but there's 400 people in it, and they all seem to be doing fine. Emily, do you, do you, do you have any more details on that? No, not really, but we're, yeah, I mean, we're measuring their symptomatic AEs and we're You know, we don't know yet the culture results. Yeah, Emily is measuring the quality of life. They all seem to have the same quality of life, so we do know that. But, you know, I, I would say that like Chuck, I mean, there's really no Replacement drug for hamazole. I mean, the theso is the best at protecting the marolide, I think, in all those other combos you mentioned, you worry about merolide resistance more. Uh so if you lose the Themaso. It it's, it's a tough road to hoe, and you gotta, you probably definitely need, excuse me, 3 drugs. I'm very comfortable with the 2 drug Azhamaal regimen. So airothabio, the the panel is fairly comfortable with using that if you have to. Um, azithro and an and an inhaled form of amicca. Kevin, you just published a paper on M obsessis with a subgroup of patients being on that regimen and what happened? Yeah, well, they're all Dave's patients. I got resistant. Dave's patients. I'm just kidding. They're mostly my patients. Yeah, we, I think we showed that uh Clofaz was not an adequate protector of sorry, it was a Ziroclofas. So I mean, I worry about that too here with Mac. I mean, it takes, you know, several months for Clofaz to get up to steady state and so particularly early on when you're using it, it may not protect the macrolide. At all or well at all, and I think ultimately we don't really know how well it protects my long term by itself. So certainly in that obsessus um experience, it did not protect liposolallamaca and um. And you know, you always worry about it's a compartment issue, right? You're inhaling amicca is that getting to where you need it to go and the tissue to protect the marolide there and probably not, right? So you, you worry about these things. So let me, let me correct that study had inhaled amcain and cloys, and it did not protect against resistance for developing resistance for amma, right, sorry, I said it before, right, so we know that combo that combo doesn't protect each other. Do we know anything about. Isith throw and clofazolone, Chuck? Uh, I don't know anything about that, uh, particular, I don't know if anyone else does, but I would also point out that the top line ri the data that were released, uh, this summer, um, showed a pretty surprisingly low culture conversion status in the two drug arm of Ezithro and hambutal, uh, compared to the Azithroathambuttal, uh, air case arm. Um, and so that that was at 6 and 7 months. It could be they catch up by 12 months it'll be the same, uh, but, but at least at 6 months it was surprisingly low. So we'll have more data on that Azithro with Abiol compared to azithro with Ambitol in our case. Little, little more pedestrian question. You mentioned Rifabutin. Um, I've never, I've never met anybody who liked Rifabutin, um, who did what with like Rifabutin. I mean, that's always well, it's not recommended, and, but we do have patients who tolerate it sometimes when they don't tolerate Rifampin, believe it or not, yeah, introduce me, introduce me to that person. OK. All right, let me move on. OK, so her opto exam was not consistent with drug-related toxicity, and the numbness and tingling resolved actually by adding a vitamin B6 to her regimen, and she stayed off meds for several months. We actually restarted her slowly on azithro, etambuto, and rifampin again, and also with some, I think in the beginning there might have been an anxiety component certainly with the ocular issues that were going on. Um, but we added vitamin B6, doesn't always work, and there's studies that show sometimes it doesn't work at all, but in her case, uh, it did help. Um, but she was still positive after six months of treatment. So now we're all the way up to 2020. Uh, I believe even with, uh, being on top of these patients and really trying to get them in for sputums and right, you've got to wait 4 to 6 weeks for your sputums to come back, there's a long delay in being able to make changes often when you're treating these NTM patients, so she's now recalcitrant. And you can see she's also progressing so you can see the changes in that lingula. Now she's going on to much more cystic bronchiectasis, more volume loss. And I won't say that I see any disease yet down in the lower lobe, but we'll take a look. Uh, that will be coming up. So what do we want to do now that she's refractory? She's on 3 times a week therapy. She still has not converted her sputums. There are a number of retrospective studies, but we know we have one, randomized trial, uh, looking at, um, inhaled ammicain in a liposomal form. Um, most people in this room are well familiar with this data from the convert trial showing that by month 4 there was a 29% culture conversion compared with patients who just stayed on guideline-based therapy alone and remember these were patients who had been positive in this trial for many, many months, some even years, so, uh, converting a very tough group of patients. So refractory Mac. Panel, do you all go? She's on 3 times a week therapy. What would you do first? Do you all go to adding liposomal lamacain? Do you all, do you, any of you change from 3 times a week to daily therapy? Kevin, what do you like to do? I know like Kevin, you want to wait a little bit longer, give her till 8 months. No, I mean, I guess my initial comment was, sorry, I got a frog in my throat. Um. Maybe we should have treated her 6 years ago instead of watchful waiting, and none of this would have happened. I'm just to be, you know. That's why we're presenting this case. Yeah. I mean, I have a hard time with the watchful waiting term and and even the concept sometimes, but I mean this might be a good example as to why we don't want to watchful wait sometimes we should treated her, but in terms of where she's at now. I mean, I, yeah, I mean, I, I, you know me, I like daily therapy. I don't like intermittent therapy. Um, I would have had her on intermittent therapy, or on daily therapy a long time ago, but I certainly would switch her to daily now, and I would, I would put her on Alice. I think that's the Right thing to do. So I, I think it depends on what way she's not responding slash which way she's progressing. I mean this is kind of a slow burn. She's, it's still localized, uh, it's not spreading. She's not sick or. She has no, no symptoms now. The cough is gone. Right, so I think you got a little extra time to try the 7 day a week, uh, and see where, you know, put it, put, you know, you have to put a beginning, a middle and an end to it. You try X number of months and see if you can contain it, slash see if you can get people to convert the sputum. But you know, as I said, and somebody who's not sick and it's still localized and it's, you know, like that, it's almost, it's interesting, it's the anatomy of for bronchiectasis that's changing. It's like a right, it's like a vas are still positive, yes, right, so you know, I, I, I, I, I think I could live with 7 day a week for a little while. Before going to like, yeah, so I, I look and and say, uh, number one, are you adherent, you know, are you taking the medicine as prescribed? I look at, are there any concerns for, uh, drug malabsorption whether I want these levels, um, I, uh, uh, look at the drug susceptibility testing looking for acquisition of macrolide resistance. I would switch to daily therapy and anyone who's culture positive after 6 months of guideline based therapy I had. Alice. OK, so she had drug levels. Her drug levels were all normal. thank you. We sent them to National Jewish. Um, she had repeat sensitivity testing done, uh, which came back still uh sensitive to Emma Cason and, uh, macrolides, and we opted to do both. So we first changed her to daily. Before you go on, Dorian, can I just ask in check in the timing, rhetorically ask when do you do TDM or therapeutic drug monitoring? When do you check? Serum levels in this way because she was on thrice weekly is it when you go to daily therapy? I mean, and I, I again, I realize this is almost rhetorical, but I think for the group it would be helpful to understand what your practices are when do you, when you treat drug or when do you check drug levels things if I'm doing drug levels to because I'm concerned that that may be one of the reasons for treatment failure, then I would do it with what they were taking um. And uh I may do it again once I switch them to therapy because now I'm again concerned this person for reasons I don't understand are not absorbing their meds so once I get them on daily therapy, I would probably consider checking again um. And to be honest, you'll be shocked how many people have levels that are lower than what you thought they were, uh, going based on guideline based, uh, treatment recommendations. Can I ask what that means is a whole different debate. How long does it take you to get your level levels back from the time you send them? Uh, but Shannon a week, 3 weeks, right, about 3 weeks for us, but we, we make sure well we have our, our instructions per national Jewish, so, but we make sure they're on the, uh, consistent schedule, same time in the morning, even if it's 3 times a week or daily, and then we will do an early and a late draw, um, on those days they spend the morning and part of the afternoon at our office and we'll do that, um, um, so. Hers were done and they were normal so we didn't repeat them. We, we changed her to daily. We ordered our case uh at that time, um, she started that about 2 months after starting daily meds and she was, uh, still culture positive for the first few months, but at month 5 she developed a diffuse pruritic mild rash and now remember she had been on meds for a long time. But it was really troublesome, did not respond to low dose prednisone creams. All meds were stopped. She stayed off medications actually for almost a year because now it was COVID, delayed getting her into just about everybody, uh, derm room biopsies were done. She didn't wanna have to come and do monthly labs and come into the office. She was remember feeling totally fine, did not really want to come to the hospital for anything. The rash ultimately resolved without really any intervention. A diagnosis was never made, but then in 2021, she started to have episodes of small amounts of hemoptysis which obviously got her concern. She returned for care, uh, and therapy was restarted in 2021. But what you see on this chest CT scan was very concerning because now we see that she's got superior segment disease, she's got some bronchiectasis you can see here, uh, progression um with more nodular opacities in her lower lobe. Um, and let's see if I can, and just continued areas to show that she's got some now lower lobe disease. You can see here, uh, she's got some lower lobe disease, one of the branches off of the superior segment. So when to consider surgery. So I know Kevin's gonna say back in 2014, we should have done surgery, started all meds, and that would be done, and she would have been cured and we wouldn't have to be dealing with this now, uh, almost 9 years later or eight years later. So when to consider surgery, refractory to antibiotic treatment, you know, we usually use it as a tool after patients fail, but maybe we should be thinking about doing it up front, particularly if they're young and otherwise generally healthy. Uh, significant hemoptysis as long as their baseline pulmonary functions permit it, localized disease usually, although there are some patients where debulking, uh, especially if they have a large cavity, and that's the cause of their problems, even if they've got some scattered disease elsewhere, um, if they have resistant organisms, you need an experienced surgeon and you need good follow up pre and post-surgery and often good antibiotic regimen that they can tolerate pre and post-surgery. Um, Doctor Mitchell at National Jewish and University of Colorado has has published on the largest case series, um, and looking, and this is way back in 2008 where mostly, um, bats and open thoracotomies were being done and even back then fairly low mortality, uh, morbidity of 18%, um, and, and these were very sick patients for the most part, um, and most of them did, uh, relatively. Well, and robotics has now come into play, uh, faster recovery times, less postoperative pain. I know many centers, including Doctor Mitchell are doing robotics and I I always like to just our little series that we published, um, in 22 to look at our patients, the 1st 13 surgeries, they did really, really well. Most of these had cavitary lung disease with Mac. Uh, we had one surgeon that was doing all of our. Surgeries a range of length of stay was very short. No conversions to open, no ICU stays, etc. All patients ended up coming off IV antibiotics, and the majority of patients came off antibiotics completely and converted their sputums. We looked at a larger double another uh 12 cases, uh, 27 procedures that was presented at chess this year, and again. Uh, 22 of the 24 patients did very well. They had very short hospital stays. Uh, there were a few postoperative air leaks, but we can send them home with a, uh, a tube. Our, our surgeons send them home with a flurova tube and it's monitored from home. Um, 11 required a thoracentesis, but we did have two patients that went for salvage therapy, one with very diffuse cavitary disease who had. Very large pneumothorax that could not be uh resolved with chest tubes alone required resection, and she ultimate ultimately expired and then another very advanced patient so really telling us that surgery like this is really for the early localized patient and really is not very useful in patients who have very extensive disease who are already very, very sick. So, when do you consider surgery? Chuck, at this point, do you think you would have operated on her earlier? Yeah, I, I think to, uh, Kevin's point we might have compressed this over time, you know, and, and we would have had a much shorter case presentation, but again, the patient's part of this discussion and if they're not interested in proceeding, then you know you try to document, uh, the risk and benefits and then you go from there, um, but. You know, I, I, I do think that it's an important point which, uh, is that, uh, who does the surgery is very, very important. These are difficult cases. uh, Doctor Mitchell, who we work with, uh, has done so many of these, uh, these patients that, um, we feel like we, we're making decisions about who should go to surgery and who should not, but we don't have very good criteria for that and so it gets into the art of medicine. Uh, it's very hard for me to, to, to easily share our decision making process at a patient level. You know, with everyone, and that you would have come up with the same decision that we did. Um, and, and, you know, I don't forget how many pneumo pneumonectomies he's done this year, but I mean, you know, take, you take on very difficult cases sometimes, uh, and, um, uh, it's, uh, if you're gonna do those kind of cases, you've got to have the right, not only surgeon, but the right team. OK. I think it in this case illustrates the, the double-edged sword of it or whatever the mixed feelings about it. I mean, the, the conversation at the beginning is the patient's not sick, what's the rush? Patients not sick, what the rush and now we moved to, we should have done everything sooner. So, you know, it's, that's, that's difficult when, when things, when patients have some features from one column and one feature from the other column, uh, you know, we try not to learn from hindsight, but it's, you know, often, often, that's the only way you learn. Uh, and the other thing is, you know, one of the problems with cavitary disease is depends because this patient has such localized disease, you can almost quote promise them unquote a better result and somebody will, you know, will debulk and we'll take out this one and this one, but you realize you still have disease in, in multiple other areas, and we hope that by debulking that we'll have an easier cha an easier, uh, um, uh, uh, easier road ahead to be treated with antibiotics. So that that's always a consideration. Can I say the the red flag in this case though, um, was a smear positivity. Uh, you have non cavitary disease but it's persistently positive smear and then you look at that lingula we know that when we take these, these lungs out and look at them under the microscope, there are no blood vessels in them. There's no way to get the blood into where the infection is, and in this case they had an unusually high bacterial load for non cavitary disease. So and I, I do think that there was a red flag early on. Um, but That's the way it is. I, I mean, the last thing I'll say on that front is that if she had symptoms, this all would have been different or if she was coughing up blood back then would have been a no. And I'll just say quickly too because this is where you want to be able to look at a number of these patients who are asymptomatic and follow them all. We know the cases where they like this one so that's where you come in, Emily. We need to follow the asymptomatic ones, yes, because they really sometimes are missed in a lot of our, and we can't enroll them right unless in any of the trials too unless they have a significant predominant symptom, so we are missing those patients. Um, OK, so things weren't good. She became smear positive again on 3 times a week treatment. We rechecked her. We added IVMiccain, we increased to daily meds like we said, and we just bit the bullet and we went on. She agreed to have surgery finally, specifically because we told her the disease was spreading to other parts of the lung and then we, surgery was not gonna be an option ultimately. She did really well. Uh, she had a lingulectomy and a superior segmentectomy on the left. She was in the hospital for a day. She did have a persistent pleural effusion postoperatively, causing some, uh, progressive persistent shortness of breath, which was resolved with simple drainage in the office, and she continued IVMA case in 6 weeks post and daily meds with a plan for 1 year post-surgery. And you can see her scans postoperatively um which show this is her surgical uh line uh the the lingula is gone. She still had uh some amount of disease, uh, in the lower lobe, um, and I will tell you, uh, that she is now. Culture positive again and so um at this point she was, she was still on drugs. She's like at the end of the year of drugs, so we're considering that she's recalcitrant again. Um, may put her back on liposomal lamacain or we may enter her into one of the trials, um, particularly she would be a candidate for the epirobial study, which is a new antimicrobial boron containing antibiotic that is available for patients who are recalcitrant, who aren't, um, who have also failed liposomal lamicain or for some reason can't use liposomallaication. And soon to have we soon will have an inhale clofazamine trial started here. I know there are other centers right now that are doing inhale clofazamine so we might have eliminated all of this before she had lower lobe disease and gotten rid of the lingula much earlier but you know we didn't have that crystal ball and and it is very difficult when patients are minimum. symptomatic, um, to ask them to do a surgery which potentially could have very low percentage but if you're that one who has a lot of complication after it's very difficult to send someone who's asymptomatic. So, um, that is that this case uh I just wanted to put all the guidelines and had up a number of the, a number of the societies like ERS and Chester. Coming out with new guidelines soon and I do want to point out um there are some great articles on managing MAVM and M obsessis by uh you can see some of our experts here Doctor Daley and Doctor Griffith in ERS and I love this one on treatment of mycobacterium obsessive pulmonary disease by Doctor Griffith and Day so I refer you to these and we will, uh, thank. My phenomenal team here at NYU, uh, there are many people not on this slide. We have other phenomenal MPs as well, Sana Assad and Molly Martello who have joined recently, as well as a large cadre of research associates, dietician, uh, and you name it, who have been working with us to really try and take care of these patients. So thank you and we'll take some questions. Mm Do, yeah, I just have a quick comment. So back to the therapeutic drug monitoring, I just wanna emphasize that when you change from 3 times weekly to daily, oftentimes what I see is what you suggested, going from 500 mg of azithromycin down to 250 daily. And there's actually data to support that we are underdosing when we do that, and because we continue to use the 600 mg of ourfampin. It's a, it's a point in time to repeat drug levels because I worry that we're giving patients subtherapeutic doses of azithromycin on daily treatment. So, just a suggestion, once you move to daily, I would repeat drug levels on every patient. On someone that you can are concerned that is refractory and concerned for um maabsorption, just recognize that interaction is real and you could be moving from a therapeutic window to a subtherapeutic window by making that change. OK. So we'll remember that because we test everyone who's recalcitrant right now, but we don't pay attention. If they're on the 500 and we're OK, we don't think about retesting when we move them to daily. So we will, we will think about that definitely. Thank you. Um, go ahead, Kevin. Oh, I was just gonna add, I mean, I, I know it's not in the guidelines to do it, but I, I check everybody. I start treatment after 2 weeks. I check there Zithromycin and they all because early on, I, we didn't publish it, but about 15% of the people that we saw in our clinic were Had quote unquote low levels to at least one of those drugs, and so I just do it routinely. I don't have any data to say it changes outcomes, but it does at least uh make me feel assured that the patient's absorbing and I don't have that issue later cause I check people up front, so. Shannon, there's a question online. If your drug levels are subtherapeutic, how do you adjust the doses of the antibiotics? So, obviously, if you're on 250, you can go up to 500 and then repeat testing. What do you do for theambuto or rampin? So fortunately, we rarely see Rifampin malabsorption. Almost always rifampin levels are within target concentration. And again, there's no data behind the hambutol piece to try and reach a certain therapeutic window. There is data behind reaching a certain window for azithromycin and that correlating with microbiologic outcomes. So we engage our, our pharmacist, our farmD to try and Increase the dose of hambutol on repeat levels, but there's really no science behind that. OK, thank you. Here's a good question. How often do you screen for NTM if you have a patient on chronic azithromycin? So since we're getting sputums every time they come in, usually every 3 months, we'll be screening every 3 months, but is there, there's no guideline out there to tell us how often to screen. And if they have NTM or had it, how long do you wait before considering consider adding on azithro for exacerbations? So that comes up frequently. Someone will have sputums from 2020 or 2021 that have NTM, and the last two years they don't grow it any longer. Is it safe now to put them on prophylactic 3 times a week, azithromycin? Doctor O'Donnell shaking her head. What do you guys do? I, I wouldn't, but I know what Doctor Griffin would say. Yeah, I think you have to individualize it. Uh, there are patients who are having frequent exacerbations. It's really affecting their quality of life, uh, and you know, potentially they're there could be mortal. They get a pneumonia. So I, I think you have to do what you think is the most important. Interventions to decrease their frequent exacerbations. So if I have someone who hasn't grown back for years, uh, and I've been sampling, you know, to make sure it's not there and it's always negative, I'm very comfortable doing it. Uh, but I think that's the key. People come in, they go, Oh well, yeah, they haven't had Mac for years, and you look, and they had one culture and, you know, two years. That hasn't convinced me they don't have or the quality of the sampling is typically low, so I don't feel like I can trust it. I mean that that's my problem and, and in Japan this is they don't even discuss this. This is, uh, they just begin erythromycin. Instead of uh azithromycin, so they're very comfortable using low dose erythromycin for which there's a randomized placebo control study demonstrating effectiveness and decreasing exacerbation. So, um, why not? Yeah, that's a great answer. It's a patient tolerates it, it's a great solution. Yeah, I agree. Doctor O'Donnell, where do you think we should be going in terms of biomarkers for, you know, to tell who we should treat or not treat? Do you think, uh, We should come up with some strategy there. Cause if we had some way to assess um early on, right, who's gonna progress and who doesn't progress, that would be very helpful. So do you think there's anything that we should be looking at? I, I think right now there's some biomarkers that are being evaluated in the CF uh setting by, uh, being led by Jerry Nick at National Jewish. uh, most of those right now look to be more treatment response biomarkers than I would say, you know, predictive of progression. So, uh, I'm, I'm pretty pretty excited we're gonna have biomarkers that will look at um treatment response. I, I think predicting progression is a difficult one. Yeah, but, but going back to what you said, I think the smear, that's a cheap biomarker. I mean, the smears positive that they have a lot more there. Um, I think that's something you can use right now, but yeah, we'll have more fancy ones, I think. There's a question that was brought up that's important. Uh, when she did present to us, she was already smear positive, so we didn't have to consider doing bronchoscopy. Um, but when she did present in 2014, her smears were negative, her cultures were negative. I believe they got induced sputums. I don't know how. Chuck would say first thing to do is get a good induced sputum. Yes. And if those are negative in a patient like this, we would have gone on to bronchoscopy here to get a better sample in someone with, you know, this isolated bronchiectasis and bronchiolitis in the lingula. That's a rare patient. Most patients with induced sputums end up having, uh, positive cultures who have NTM disease, but definitely would have considered BronC back then. Um, to get the diagnosis. And then there's one last question, um, in, oh sorry, Doctor. Hey, um, so we mentioned, uh, bacteriophage therapy as a possible option for recalcitrant disease, yet it's very challenging to get a matching page just curious where we are with bacteriophage therapy as a potential option for NTM. Where are we? Um, I, excuse me, I've treated one patient. I mean, I I don't know how many you guys have, but. Yeah, well, we treated the one patient we published the cell, and, uh, Doctor Kasperbauer is gonna be treating one and there's another CF patient we're treating. The issue is, uh, this is a MAC patient, uh, and we, uh, traditionally where we've gone, which is Graham Hatel at University of Pittsburgh for, uh, uh, phages, is, uh, he's got, uh, obsesses mostly, so finding Mac ages is tough. There are companies currently developing and engineering, um. Um, page for Mac. So I think in the near future, like next year, that there will be some uh potential uh page for Mac. OK, uh, and the last question before we go on to break is when you see a patient with recalcitrant disease, um, how aggressive are you, Doctor Kamelhar, at looking at their shower heads and their water supply in their home, uh, how often do you do that? How often do you advise them? Not often, uh, because the time that I did it, you know, cautionary tale. So I had a very quickly patient who went swimming every day at the Y 6 days a week went swimming at the Y, and she developed, uh, hypersensitivity, actually hot tub lung, and she was very sick. Uh, she said, OK, we gotta, we gotta check it out. Definitely, I got it at the Y from all that stuff. Then it turned out her husband didn't go swimming. He only went to the steam room. So she had very sick Mac. He had not sick Mac. He just had it on his. He had COPD and had his funeral. Turned out when we, we send it to Fornham, all of the specimens, and they even went to the, to the health club to the Y and, and, you know, without asking anybody, took specimens from here and specimens from there, and they both got it from their home, not from the Y and it turned out that she got it from the bathroom and he got it from the kitchen. So, all the testing, all you see, you see, you see, that's what happens to people. It turned out it didn't teach us a thing. So, you know, you, you do the old, uh, you know, short showers faced away from the shower, you know, immerse it in bleach once in a while, and so on. But in terms of, uh, making that a, uh, uh, aha, uh, I think I can solve your problem, uh, you know. Right. Better to do aggressive airway clearance every day. So whatever gets in. Better to do aggressive airway clearance every day. So whatever you in here, take your battles. All right. Published December 11, 2023 Created by Related Presenters Doreen Addrizzo-Harris, MD View full profile
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