Welcome. Today we're going to talk about non tuberculosis. Mycobacterium A in a case based, guideline driven update. My name is Shannon Casper Bar, and I'm coming to you from Denver, Colorado, where I practiced at National Jewish Health and the University of Colorado. My disclosures are listed here. I have been a speaker and worked as a consultant with INS men as well as and to therapeutics and para tech pharmaceuticals. Please note that all patient case material will be de identified. This activity is for educational purposes only. CMI education, the faculty and the program sponsors do not make recommendations for the use of any specific therapies. Treatment decisions were based solely at the discretion of the patients treating position, and this is supported by an independent educational grant from instead to begin what are non tuberculosis mega bacteria? These are organisms that are ubiquitous in the environment. They're found in the soil and the water primarily. There's over 200 different species, but the most common human pathogens are listed here, with Mac otherwise known as Mike Spectrum Avian complex, making up the most common organism that we treat, followed by mycobacterium obsesses complex, which should be noted there are three different species in that complex. Mycobacterium obsesses Ms Aliens and mycobacterium bloody I. Then we sometimes see Michael victory in Cologne I or mycobacterium for to it, um, infections. But I'd like to point out that any of the micro bacteria can cause human disease depending on the immuno compromised state of the patient. For today, we're going to focus on Mac or Mike Spectrum Avian complex. I'd like you to know that the incidents of NTM lung disease is increasing, and this has been illustrated in studies from the U. S. And other countries as well listed here in this graph is an illustration from a data set of a managed care claims database involving over 27 million patients annually. And when you look at the data between 2000 and eight and 2000 and 15, you see the incidents is continuing to increase each year, primarily represented in older individuals and women more than men. As I said earlier, Mac is the most common organism that we treat. It makes up about 80% of the disease that we see in the United States, and the risk factors include not surprising older age um immuno suppressed individuals and patients with preexisting lung disease. So most of our patients in clinic have concomitant bronchi exorcists, which is otherwise dilation or abnormal dilation of the airways. Cystic fibrosis makes up some of those patients with bronchial actus is but a small fraction of those individuals. We also see patients that have underlying sarcoidosis, or ultra one on a trips and efficiency. COPD, which is a significant risk factor for NTM lung disease and certainly those on immuno suppressant medications, including those patients who have received a transplant. This publication was looking at data from Veterans Administration hospitals across the United States and understanding whether or not there's regional preferential regional patterns of NTM lung disease. And in fact, what you can see here nicely on this heat map is that the coastal regions of the United States have higher rates of NTM lung disease. This has been shown in other studies, and investigators from the NIH nicely published their work in this area. The hypothesis is that because this is an environmental organism in areas where we have a higher water vapor content, we see higher rates of disease. So this next slide I'm going to go through the clinical Fiona types. There are really two main clinical finish types on the left. Here, you're going to see CAT scan with images of a patient that has bronchi, exorcists, several areas of nodule clarity as seen in this slide, but notably no evidence of Cavite ation. Now, this individual actually had diffuse spunky activists related to a congenital syndrome otherwise known as Mounier coons. The second video on the right is an individual that has underlying COPD notable emphysema. You can see the bull and the upper lobes and then a large upper lobe, thick wild cavity. So this is Cava Terry Pulmonary Mac and the first video that I showed you we would describe as bronchi Attack Nagy, Alor Disease. These are not mutually exclusive. People can certainly have both clinical Fiona types. But as I'll show you in the subsequent slides, the treatment decisions are really based on the radiographic genotype. So in order to diagnose Mac lung disease, you need to meet specific criteria. Um, shown here in this table, patients should have symptoms either pulmonary symptoms or systemic symptoms in addition to radiographic changes. And I just reviewed those radiographic changes, so both are actually required. The next step is to appropriately exclude other diagnoses, and finally, the microbiological criteria are important. So because these organisms are ubiquitous in nature, it really takes a rigorous investigation on the microbiology side of things to make sure that you have a patient with clinically relevant disease. So the authors from the guidelines did not change these criteria for the diagnosis. However, there are some nuances that I'll point out. So patients should have at least two positive cultures from speed and samples. And if the results are non diagnostic, we would recommend repeat sputum smears and cultures. Or, if a patient has a positive culture from one bronchoscopy, they technically meet the diagnosis criteria or finally having a biopsy with concomitant micro biologic. I'm sorry, micro bacterial histological features such as granulomas or FBN sneer and an additional positive culture, either from the biopsy or from a bronchoscopy or sputum. Importantly, the labs are now able to tell us the species of Mac, and in fact, there's 12 different species of Mac, and so we would recommend that identification to the species level be obtained. The reason for this is that some patients, for example, with reflux disease, make culture mycobacterium a V um in one week and mycobacterium interest salary the next week. That does not meet the definition for having pulmonary Mac, so we would recommend that you have consistent growth of the same species. The other nuance from the guidelines are that multiple specimens, ideally over a week or preferably over several weeks, be obtained. And the reason for this is giving that patient time and space between their isolation, we believe, contributes to a higher yield. And potentially, um, consistent growth over a longer period of time would be more predictive of having pulmonary NTM lung disease. We would also recommend pursuing sputum induction if a patient is unable to expect it. In fact, most of our patients who are unable to expect a rate are able to culture the micro bacteria successfully with sputum induction rather than going straight to bronchoscopy. So this summer in July of 2020 the new NTM guideline statement was released. This was a multi society effort, including the 80 s, or American Thoracic Society, the European Respiratory Society, the European Society of Clinical Microbiology, Infectious Diseases and the Infectious Disease Society of America. As you can see, these are published in two separate journals, both clinical infectious diseases and as an E. R s official document. This document actually had a different format. So they use the PICO format, which is an acronym for an evidence based methodology, um, to frame and answer health related questions. So PICO stands for patient intervention, comparison and outcome. So I am going to present to you the specific PICO questions that were addressed as it relates to Macklin disease, the first of which is listed here. Should patients with MGM pulmonary disease be treated with antimicrobial therapy or followed for evidence of progression, otherwise known as watchful waiting? And with each PICO question, I'm going to frame it with one of my patient cases to help us. Um, think about this question thoughtfully. So this is a 65 year old female without any other comorbidities who was coming to me with chronic cough. Her sputum smear was negative, which is important, and she was started on airway clearance and antimicrobial therapy was deferred. So you can see on her CAT scan and I chose one select slide because she really had mild disease she had focal right middle lobe modularity, No evidence of capitation. So unfortunately, despite our recommendations for the patient to come back in six months and be followed closely, she's lost to follow up. And so she presents five years later with this CT, so she still has her chronic cough. She's not been adherent to her airway clearance, and her cultures are still positive. But what you see here over a long period of time is what we're all trying to avoid and that is worsening disease and worsening bronchi exorcists. So it's one thing to have a few new Nah, Jules. It's another to have developed irreversible changes of the airways or bronchi ethicists, which can happen with untreated infection. So I hope that this case illustrates the recommendation from the authors. And that is, in fact, in patients who meet the diagnostic criteria for NTM lung disease. They suggested initiation of treatment rather than watchful waiting, especially in the context of having higher burden of disease. So that would include patients that have positive smears or certainly any patient that has cavatelli lung disease. Those are patients that we would absolutely not pursue watchful waiting the next PICO question is listed here. Should patients with NTM pulmonary disease be treated empirically or based on in vitro susceptibility test results? In the past, we thought the macro lights were really the only clinically relevant. Um, no. Sorry between the hair and my mouth and tripping on that, I'm going to start one more time. Um, the next PICO question is listed here. Should patients with NTM pulmonary disease be treated empirically or based on in vitro susceptibility test results in the past. And with the 2000 and seven guidelines, the one drug that was recommended to test when treating for pulmonary NTM was the macro lab because we knew that in vitro results correlated with in vivo outcomes, that has changed. So now we know that both the macro leads and um Akesson susceptibility test results predict how patients are going to respond to those two antimicrobials. And here's a patient that illustrates that this is a 59 year old female with a four year history of Mac. Unfortunately, a common story in our clinic. She had been on and off therapy for years, and our cultures were persistently positive. Despite ongoing three drug therapy, she had a history of intolerance to standard dozing. Therefore, she was splitting her doses throughout the day and oftentimes missing doses. And when we met her in 2000 and 18, I have her susceptibility pattern on the right. The first thing that I would point out is that she has diffuse disease, so she has areas of na jewels, consolidation, airway wall, thickening, mucus, plugging, bronchi, exorcists. And again, this is one representative slice. But this was a five lobe involvement. She also has a heavy burden of disease, is seen by her culture. She has greater than 200 colonies on the plate, noted that the first week of of Incubation and her strain was densely resistant to amicus in and clear with promises. So this portends a very poor prognosis for this patient and, in fact, into since 2000 and 18, she has required continuation of a four drug regimen with progressive disease changes on her imaging. So in patients with Mac pulmonary disease, the author suggests susceptibility based treatment for macro leads and McKesson over empirical therapy. When you order in a microbial susceptibility testing, this is performed in two different ways. First, using Fiona typically testing, which means that the organism is directly observed using broth, micro dilution in the presence of different drugs. And then you get an Ms, which most of us are familiar with in infectious diseases. These are the relevant MS cut points as dictated by CLC. So for Clara through Madison, anything over or equal to 32 is considered resistant for Ivy McKesson. This changed in the 2000 and 18 publication of the performance standards for susceptibility testing, now greater than or equal to 64 is the cut point for resistance and IBM Akesson. It's different if you are considering amicus and lip Osama inhalation suspension, so that cut point is actually greater than or equal to 128. The other method for antimicrobial susceptibility testing is genetic testing, with the great advance advance of rapid turnaround. So with Jenna typical results. We get a turnaround in a matter of hours or days, as opposed to the peanut IPIC results, which can take weeks. There are two main mutations that we're looking for um, that are consistent with resistance to macro lights or mini biggest sides, which is the R r l mutation for macro lead resistance. This has a very high sensitivity and specificity. The R. R s mutation for me. Neglect. Besides, you lose, um, sensitivity. However, it's highly specific of note. We do perform this here, and we always back it up with a typical results as well. The next question is, Should patients with macro light susceptible Mac lung disease receive a three drug regimen with a macro light or without a macro light? Basically, looking at what is the importance of the macro Lied in these regimens? And I show you hear the results of a systematic review, including 21 studies. And you can see there's a significant difference between those regimens that were macro like containing versus those without so 38% success with a macro lib free regimen versus 54% with a macro like containing. It's important to point out that speed, um, culture conversion in these studies increased in macro like containing regimens as the quality of the study improved. So the authors recommend, when you're treating macro light susceptible Mac, you should be using a macro light. It is regarded as the most important drug in the regiment, and we also know that when we develop macro light resistant lung disease, the outcomes dramatically change some studies suggesting treatment success as low as 5% in those individuals moving on to the next question in patients with newly diagnosed mackerel, it's acceptable. Mac should a Z three mason or clear information be used? Well, here's a case of an 80 year old female with chronic bronchial Tadic. Modular Mac. She's been on therapy with Clara through Mason, the theme tall and rampant. And the first thing you noticed from this test X ray is how thin she is on treatment. She had notable appetite, loss, dyskinesia and weight loss. Her BMI, when she came to see us, was 16.5. The only change we actually made at that first clinic visit was getting her off the clear through medicine and switching her to a safer medicine, and the patient reported appetite improvement within a week. Three months later, she'd actually gain £10 which is an enormous amount of weight in this thin woman. I'd like to point out that multiple studies and NTM lung disease not just map but also Michael Vick term obsesses have shown that low BMI is associated with disease progression, so we regard weight and weight restoration as important as any antimicrobial that we're using. It's really critical in the treatment, so in patients with mackerel, it's acceptable. Mac, the author suggests a zip through mice and regimen over a clearer through mice and regimen, not just because of the side effects that I've just gone through but also because of less drug drug interactions and single daily dose ng. Should patients with Mac pulmonary disease be treated with parental and moccasin or streptomycin? Listen or without those agents in their regimen? So here's a 20 year old female who had metastatic cancer to her lung, requiring a left lower lobe back to me, chemotherapy and radiation. And you can see from this CAT scan. She has significant destruction of that remaining left upper lobe. She has a cough, and her bronchoscopy is smear positive and culture positive for Mac. So in this individual with, she has both we would regard as severe disease and cava terry disease. In addition to being on daily treatment with a macro lied, preferably azithromycin, lithium metal and revamp in, she should receive parental eliminate like aside either in the case in or struck tennis, Um, for the first 2 to 3 months. So those are the patients that you would consider parental Munich like asides, having cavatelli disease, advanced or severe disease or the third category that I haven't yet mentioned are those patients with macro lead resistant disease. Those are the patients in which you would begin parental neglect aside, in addition to their three oral agents. The next question addresses, I mean, besides in a different administration. So in patients with mackerel, it's acceptable. Mac, should a regiment of inhaled McKesson or without be used for treatment? Well, we actually have excellent data to answer this question in the form of a randomized controlled trial. So on the right here you see a bar graph describing the results of a randomized control trial looking at amicus in liposomes inhalation solution. When added to guideline based therapy, patients were randomized in the 2 to 1 fashion and then followed with monthly sputum cultures and the primary outcome here was the proportion of patients who were able to achieve a negative culture, and you can see by month four even occurring as early as month. One a significant difference between the two arms. And in fact, this had a P value of less than 0.1 So approximately a third of patients who are in the treatment arm were able to achieve culture negativity versus 8.9% in the background guideline based treatment arm. So this is I'm going to show you Now, a case of mine in a 56 year old female who had what we define as refractory Mac. The way we define that is being culture positive. At six months, she had received actually a year of daily, as it's reminiscent of family to and rampant, and the reason why she was placed on daily treatment was that she had multiple small cavities throughout her lungs. And I'm showing you one illustration of that. You can see this anterior left upper lobe, small cavity ation. She had persistently positive cultures, unfortunately, maintained macro light susceptibility. So when we met her, we put her on Alice or am a case in liposome inhalation suspension. And it was with the addition of this agent that she was able to convert her cultures and maintain a year of negative cultures. And I'm happy to say has been off treatment for now at least a year. This I'm showing you her CT scan at the end of treatment, where she actually had closure of that cavity that I showed you on the left. So two answers here to this question. In patients with newly diagnosed Mac pulmonary disease, the author suggests, neither inhaled a moccasin of the parental version or, in the case in liposomes inhalation suspension to be used as part of their initial treatment regimen. However, in patients with Matt Palmer Disease, who had failed treatment after six months of guideline based therapy, the authors recommend the addition of Alice to the treatment regimen rather than continuing a standard oral regimen alone. And this is one of the few strong recommendations with moderate certainties in the estimate of effect in patients with mackerel. It's acceptable Mac, should a three drug regimen or a two drug regimen be used for treatment. So most studies have actually evaluated three drug regimens, and there's only one randomized study of two versus three drugs. Unfortunately, this was underpowered with several method, a logic, weaknesses, the representation of their outcomes in intention to treat or protocol are listed here in this graph favoring to drug treatment, but not statistically significant. There's also the concern about the development of acquired macro lead resistance. So what I can say from the authors are that they suggested a three drug regimen and not a to drug regimen. For the time being, there is a large multi center trial ongoing, which is looking at this question in patients with bronchial Tadic modular disease who are macro lens susceptible. I would also point out that in the two drug arm, the two important drugs are the macro lead and a famous hall, not a macro lied and rampant. And why not a macro light and revamp it? Well, we know that a macro lied and revamping together is actually a risk factor for the development of macro light resistance. So we do not want to use those two drugs alone. We use the family tall with the macro lied because we believe that the hospital is important at protecting from the development of drug resistance to the macro lied so in patients with macro light susceptible Mac should daily or three times weekly regiments be used well, here's another patient of mine 78 year old female who had six months of cough before she came to see me. She was diagnosed at an outside institution with Mac. She had mackerel, It's susceptible disease and her provider. It started her on a zip through Mason, a family tall and revamp in every day without staggered introduction. Within two weeks, she stopped therapy due to severe GI intolerance, and she started to believe the old saying that we hear quite a lot that the treatment is worse than the disease. And that's really unfortunate, because I really do believe that we have tools to be able to initiate treatment in a safe manner for patients and minimizing adverse reactions. So I will just say that cohort studies have demonstrated similar culture conversion rates with intermittent treatment versus daily treatment when used for patients with non severe Bronco Tadic nodule or MAC. So this is not for patients with severe disease or cavatelli disease. We know the intermittent therapy has less adverse events and better completion rates, and importantly, there's no evidence for increased macro allied resistance. I would also suggest that if you're starting a patient on treatment, you pursue staggered introduction um, for my patients just to make it simple. We do it alphabetically. So in Week one, I started Zipper Mason Monday, Wednesday, Friday, and we, too, they had the theory tall and in Week three, the roof rampant that also gives them. They're empowered to recognize side effects. And, um, usually, if side effects are going to occur early, they can help discern which drug contributed to those side effects. So in patients with non cava terrine, Ajilore, bronchitis, Jack mackerel, it's susceptible. Mac, we suggest at three times a week, three times per week macro lead based regimen rather than a daily macro lead based regiment. However, again, in those three groups of patients cafeteria severe or advanced, we suggest the daily macro lead based regimen be used in patients with mackerel. It's acceptable. Mac. Should patients be treated with less than 12 months of treatment after culture conversion, or more than 12 months after culture negativity? So here's a patient of mine again 56 year old female who had contact technological er, pulmonary Mac. She was started in treatment in January of 2000 and 19 and are outside pulmonologist had recommended 12 months of treatment with three drugs Monday Wednesday, Friday. Now I agree with the intermittent therapy for her, based on the radiographic genotype in January 2019, she had project assists and modules, and I would not have graded her city as severe or advanced. However, she was prescribed a 12 month duration before she had had any monitoring for cultures, so she just stopped. In January 2020. Now, six months after stopping treatment, she started coughing again, and this is now summer of 2020. She has sputum cultures last fall that are positive, and by the time she has another cat scan in January this year, you can see that she has developed a cavity in her left upper lobe. So 12 months of negative cultures actually requires cultures. And this is really an important point. I believe, because I see this happening a lot in clinical practice that patients are not pursuing monthly or every other month cultures, and this is really what guides our treatment. And we recognize that having negative cultures for at least 12 months improves sustained culture negativity thereafter. So the authors recommend that patients with macro light susceptible Mac be treated for at least 12 months after culture conversion, and I'll use this moment to reinforce the importance of airway clearance and sputum induction. So we often recommend that if patients having a difficult time, expect a rating on their own to pursue speed of induction and what we hear back from community providers. But that's just not available in their area. They don't have respiratory therapist and their outpatient clinics. They can't send the patient to the hospital to get a speed of induction. But you know, these are tools that we offer to our patients all the time as a form of airway clearance. So once you give a patient a flutter valve like an Arab ika and you set them up with a compressor and hyper tonic sailing at home, they're effectively doing their own speed of induction for their daily airway clearance. And in that with that effort, they can provide you with a higher yield specimen at home. So here's the table of the recommended treatment regimens for Mac, starting with modular bronchial asthmatic disease. We recommend three drugs, including again the macro light, being the most important drug with as its promise and preferred revamp in anything recall would recommend dozing this three times weekly for cavatelli land disease. We'd recommend those same three oral agents but administered daily with the addition of Ivy Dominica like asides. Now, if you're using a parental, um, you look like a side that can be administered three times weekly to minimize side effects for refractor in lung disease, otherwise known as having cultures at six months of treatment that are persistently positive, those patients should be administered daily treatment with their oral therapy and have a moccasin liposome inhalation suspension added to their regimen. There may be some individuals that you consider intravenous treatment if they're refractory, such as those that have developed cavities. But at some point in time, you will be discontinuing their I V treatment because of, um, intolerance. So usually after 23 months, patients have some form of intolerance. And at that point in time, I would transition to amicus and Liposome inhalation suspension Alternative drugs to consider if you lost one of the standard drugs would include Cliff Azmin moxie flocks Assassin Lynn is solid or two diesel it or burdock one. So in summary, NTM lung diseases increasing in incidents. The new guidelines were released last summer. The diagnosis recommends species level identification and thrice weekly therapy for non severe bronchial Tadic. Modular disease is appropriate and should be considered because it has less adverse events and better completion rates. Now cafeteria or severe lung disease is treated with daily oral therapy. An intravenous and medical decides for the first 2 to 3 months. A goal of 12 months of negative cultures requires student cultures every 1 to 2 months on treatment. Don't forget about airway clearance and consider hyper tonic sailing therapy at home to improve the yield of your cultures. And finally, for patients that have treatment refractory disease. Um, Akesson Liposome inhalation suspension should be added to their background guideline based therapy.
