Video A Clinical Outcome and Success Roadmap for MAC-LD Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides A Clinical Outcome and Success Roadmap for MAC-LD Overview greetings. My name is chuck daly. I am the chief of the division of mycobacterium respiratory infections at national jewish and professor of medicine here at national jewish in the University of colorado. I'm very happy today to be able to present on a clinical outcomes success roadmap for MAC lung disease. We're going to focus on three kind of subparts. one is, what do you monitor when we're treating patients in terms of clinical radiographic and microbiological parameters? What are the triggers that might make you consider escalating therapy beyond the typical oral regimen? And what is the evidence in trial based options for intensification of therapy? Before I begin, I would like to um just share my disclosures with you. I have research grants and contracts as well as have served on advisory boards and data monitoring committee with companies that have interest in both TB and NTM. So first let's just get on the same page. What? R. N. T. M. These are environmental bacteria and now there are almost 200 species and subspecies of NTM they're found in soil and water that can produce both pulmonary and extra pulmonary disease. Although pulmonary diseases, the most common side of infection Among the 200 species, the pathogenesis varies greatly. Some species never seem to cause disease in humans were others when isolated usually do. And there are high levels of in vitro resistance among most all of these species and that makes treatment complex and unfortunately the outcomes can be suboptimal. We're gonna focus on Mac today. So it may be um complex because this is the most common. NTM pulmonary pathogen And I just like to make the point that they are now About 12 species and subspecies of mac. Very recently. My Quebec team camera and my Quebec tIM young and dense have been made subspecies of my Quebec tIM intracellular ari. So this taxonomy continues to evolve. But the point here is all of these have been associated with disease in humans. The most common to cause disease in humans, particularly pulmonary disease or a. V. Um Intracellular Aryan Camera, you're going to be seeing more and more of these infections in your practice. There's certainly a high incident or incidents and prevalence in older ages and women we even see higher prevalence is than we see in TB in many countries that includes north America, um much of europe, some parts of asia and in the same places we're seeing increases in prevalence bronchitis is is by far the most significant risk factor for NTM pulmonary disease probably followed by COPD. This is to make the point that you're going to be seeing more of these cases. These are data from a national managed care claims database. This was optimum. Uh it includes about 27 million people annually. What you see here is prevalence over time from 2008 to 2015. The top line that you see increasing their across this timeframe For those that are 65 years of age and older. So very clear they have a very high prevalence and its increasing fairly significantly. The next line are those enrolled in Medicare. So another proxy for age. The third line from the topic of women. So we can see that women have a higher prevalence than men and that is also increasing. So more of these patients will be coming your way. But we knew this. So we decided it was time to revise the NTM guidelines that these were published in clinical infectious diseases and the european respiratory journal last year. For the first time, these guidelines were sponsored by four societies, the american thoracic society, the european respiratory society, the european Society for Clinical Microbiology and infectious diseases and infectious disease society of America. So to pulmonary and to infectious disease societies, We put together a panel of 17 content experts. We had to methodology ists a medical librarian and a patient advocate. We had to scope the guidelines because this is a very large field. We decided to focus on the most common presentation which is pulmonary disease in adults. We didn't take on HIV or other forms of immuno suppression or cystic fibrosis. There are other guidelines that address them. And then of course among those 200 species we really had to focus. So we went with the four most common causes of pullman urgencies in most areas of the world that would be Mac Kansas city zen a pie and obsesses. We use the great methodology In doing so. We came up with 22 PICO questions And 31 recommendations, seven of which focused on Mac. And unfortunately the evidence base in this field is not very strong. And so we were only able to come up with four strong recommendations. Rest were conditional and using great methodology. When you read the guidelines, you'll see. We use the term suggests in that setting. So why should we make an early diagnosis and start treatment? Why is this important? Several studies have shown that disease progression occurs within 3 to 5 years and about 60% of persons who meet the 80 S. I. D. S. A diagnostic criteria. And that's only again follow up of 3 to 5 years. If you had followed these same patients for 10 years, that number would only go up. We and others have documented lung function declines in patients over time. This is more significant in those who are untreated And the five year old cause mortality can be quite high, anywhere from 10 to 33%,, Mortality is higher and the untreated than the treated 33-22%. So this is a morbid and potentially mortal illness and therefore we think that it needs to be diagnosed early and we need to consider initiation of treatment early. Now we do that using diagnostic criteria. This is really a guide for you as a clinician. Uh these particular criteria have not been well validated. So it's hard to come up with very accurate positive and negative predictive values. But using these criteria, we assume the patient has symptoms, they have a radiograph consistent within TM But ultimately we need microbiological confirmation that would be positive cultures and at least two separate sputum samples and that would be of the same species. And remember they're up to 12 max species and you often don't know that. But there are people who will grow one avian and one camera and technically that is not. That does not be criteria. Now, if you can't get sputum or their negative and you still suspect that the patient may have pulmonary NTM a positive culture from at least one bronchial washer lavage is considered um criteria that will or meets the criteria and that you can also use lung tissue as long as it has appropriate histone pathologic findings and a positive respiratory culture. However, of all these criteria, the one that we have data that tells us something about risk of progression or spewed him not from Savage and not from biopsy. So the more positive cultures you have, the more likely the patient will progress. Um, over time, one of the first things we did in the new guidelines was try to tackle this history, which is, do you treat or do you do what's called watchful waiting? This is the recommendation from the guidelines and patients who meet the diagnostic criteria for NTM pulmonary disease. We suggest initiation of treatment rather than watchful waiting, especially in the context of positive acid fast bacillus sputum smears and our cavatelli lung disease. Now there's not a lot of data to really help us with this, but it's starting to accumulate. But when you think about it we know their host factors and there are also organism factors that are associated with progression. For example, as I mentioned before, some species are just more pathogenic than others and we also know in immunocompromised patients they're more likely to progress. We also know from Cohort studies like the one here that bacterial load and radiographic extent of disease are also strong predictors of progression. So those are very helpful for you clinically when you're trying to make that determination is this patient, someone who has a positive smear in the setting of cafeteria disease, that patient is going to progress Now, there are other predictors that have been looked at like older age, low body mass index, usually less than 18.5 comorbidities. Some laboratory things like low albumin anemia and elevated inflammatory industries. These have all been associated with progression. This is just an example of one study where they had almost 500 patients with treatment naive MAC pulmonary disease who met at cydsa criteria and again over a median of three years but up to five years, almost two thirds of the patients um progress. So uh that's where the data comes from now, we recognize not everyone progresses during that timeframe, But in this study about 24% were stable and interestingly half of those patients have spontaneously converted back to negative. So I think studies like district will continue to occur and be helpful um finding those predictors of progression, those that we need to start and those that we can feel more comfortable going into watchful waiting, there's always been a little bit of concern if you do the watch waiting approach that people will progress uh and suffer from that. So there was a recent study from Korea that looked at did watchful waiting impact the the outcomes Pretty large study, 712 patients who were treated for six or more months. They define the waiting period is the time interval between diagnosis and treatment initiation. Now that waiting period was usually around five months, but you can see the range was one that almost 21 months and they showed no association between the waiting period and culture conversion or death. So at least in those two outcome measures it didn't seem to impact, meaning whether you started immediately or whether you went through a waiting period once you did start therapy, they showed that six months culture conversion was negatively correlated with death, meaning that uh that you want to achieve culture conversion because by doing so you decrease death. So their conclusion was, it was reasonable to use a waiting period, but given the survival benefit, achieving culture conversion is an important goal. So this is the first I think attempt to try to look at this issue is a waiting period safe and doesn't impact the patient. And at least in this study. And these two measures that did not, and when I talk about watchful waiting and and I say you're not treating it, what I mean is you're not starting out of microbial therapy because most of these patients have underlying bronchi exegesis and in that setting airway clearance is very important. So during this watch waiting period uh you know, we would strongly encourage if they are not on airway clearance to begin airway clearance, whether that's up pep valve of best in hell. Saline or all of the above. This is I think a very interesting study that looked looked at patients with NTM lung disease who did not initially receive antibiotics and there were 77 patients. And what they did here was they evaluated the effect of chest physiotherapy. This is retrospective. Um and it turns out that about 50%. So half the patients did receive physiotherapy at baseline and then they followed them or not follow them if they looked retrospective to see what was happening to their cough over time. And they reported that cough decreased at 6, 12 and 24 months in the subjects who received the chest physiotherapy. So that's pretty significant. And you can see that in the figure here, the top or those who did not receive chest physiotherapy. Uh and those who did and you can see the call kind of stayed the same. But in those who got the chest physiotherapy in the bottom panel we can see cough drops significantly. They also showed a significant increase in the percentage change of total lung capacity and those who received chest physiotherapy. So both a clinical and potentially physiologic benefit of airway clearance and indian patients. So this is something we strongly encourage. If you are going to initiate antimicrobial therapy, then you need to really sit down with the patient. And this should be through shared decision making and you should share the goals that you're each trying to achieve. You might want symptom relief, radiographic improvement, microbiological conversion. All of the above A patient may have different goals. So you need to be on the same page at the beginning. It turns out in a in a survey that has not been published that when patients were asked what they would like to get out of treatment. Culture conversion. I was stopped at the list followed by symptom improvement. You may say why would a patient care about culture conversion? Because they know that that is what determines the duration of therapy. So that's a very important milestone for patients. You want to set these expectations. This is very important because they need to be realistic if they're not, you're going to be held to them as a provider later when you don't reach them. So we need to talk about how long we're going to treat the patient. What we will be measuring to see if they're responding to therapy and if they are cured how will follow them what refractory diseases and uh these are I think things that have to occur at the beginning of therapy of course review the drugs and provide uh adversity education ideally both verbally. And if you can there's now a lot of resources online where you can get written information as well. And there are now also patient online resources. These are a few that are listed here. There are others but there's really actually a tremendous amount of information now online. So these are the recommended initial treatment regiments from the revised guidelines. In this setting, we broke them down into two phenotype. So if your patient has not regular Rocket Tadic disease, we recommend three drugs. Mackerel, I based azithromycin preferred and it can be given three times weekly. The regimen for cafeteria disease. However, we recommend you consider addition of intravenous education or parental stripped of bison and just setting we recommend that the oral drugs be given daily but you can't give the amino galactus site intermittently three times a week. These are two studies that took that approach and these are the outcomes that they got. One was from texas. One was from a study that I was involved in in Seoul so these are the number of patients you can see unfavorable outcome, meaning those people who did not convert their cultures to negative was 12 to 24%. Let's just say around 20 favorable outcome is pretty good, 76- 88%. Um I think many people don't understand that. That is what we expect to see in terms of sustained culture conversion. But once you get to that point, Recurrence is still very common anywhere. From 29 to 48% of the patients who were cured. Um they record And if you use pulse field or a molecular technique called rep PCR it looks like about 75% of those recurrences actually had reinfection. So you did in fact cure almost all your patients. But when they recur it's usually a new infection. So let's start treatment. So what would we expect to improve? Very little data actually on this? This is a study from Korea that I was involved in. It's a retrospective study of patients with treatment naive non characterize max lung disease. Again from Samsung and Soul 217 patients, They were treated with a standard three drug macro light based regimen. All received daily therapy before January 2011 and intermittent afterwards, I've compressed the information into one table but there was no statistically significant differences between daily and intermittent therapy in any of these categories. So no differences in outcomes improved with both dosing regimens and this is what happened. So symptomatic improvement, 75-82% improved Radiographic improvement, 68-73% culture conversion, 67-76. And that occurred quickly in about a month's time. So if I'm seeing a patient I'm expecting that these are three things that should improve. But the issue is they don't all improve. So getting a home run where the symptoms approved, the radiograph improves and culture conversion occurs. That does not happen in everyone. And that's just an important concept to consider. But what we focus on so hardly is culture conversion because it actually determines the duration of therapy. And as you'll see how we define failure. Now it turns out there's also um some correlation between these symptoms and improvement and their culture conversion. This was a study published by David Griffith that looked at patients with Mac lung disease and what you see on the left are those who, the frequency of cough and on the right, the frequency of fatigue. Now, these are the two most common symptoms of people who have Mac lung disease, cough and fatigue. And then you can see these are distinguished by those who converted and those who did not. So if we start off with cough, we can see at the beginning they all had cough. This is percent. But over time we see a really significant decline in cough and those who converted and you do see a decline in those who did not, but not nearly as much. And the same thing. It's almost identical with fatigue. So we tend to see these two in parallel symptoms are improving mostly in those people who are also culture converted. I mentioned radiographic response. This is something I think that's also very helpful to to see whether or not we're seeing improvement and the opacity. The top panel here 70 year old woman with M. A. v. um you can see that there was some no regularities and project assists little ground glass and that improved at a seven month CT scan with treatment. The bottom is a 71 year old with intracellular Larry who had uh this cafeteria lesion as well as some scattered tree and bud uh in broad geneticist and you can see by six months the cavity had closed. These are the kind of things we're looking for. It would usually repeat a low dose ct at around six months in people being treated. But micro back Michael back to your culture response is still the main thing that we're looking at because time of sputum culture conversion defines total duration of therapy. So if you initiate therapy on the left and let's say that by three months cultural conversion has occurred, then you add 12 months and that would give us a 15 month total duration. But it also tells us who has treatment refractory disease because here we're looking at those who are not converted and if they have not converted by six months, that person is considered treatment refractory. So just a thought about treatment refractory. The way it's currently defined is as you see here, this was published um In the European Respiratory Journal in 2018. It was a consensus document in which experts we came together and we voted on different definitions for cure treatment failure. And what came out of that process was treatment failures, defined as the re emergence of multiple positive cultures or persistence of positive cultures with the causes of species From respiratory samples after 12 more months of therapy. I don't like this definition. Um That's a long time to treat someone before you can figure out that it's not working. So why not six months? Because we do now use in the guideline six months as labeling people as treatment refractory. We know again from David Griffith in 2015 he published data on a cohort from Tyler texas, 83% of patients had their first negative culture within six months. So that's what you expect culture conversion can occur quickly and those who are going to respond and using semi quantitative culture scores, they could detect 2-3 months what was gonna happen at 12 months In a study that we did in Korea. We showed that cultural conversion by six months was highly predictive of culture status at 12 and I'll show you that here Doly large study almost 500 patients were treatment naive mac pulmonary disease. If we look on the left, you'll see that 76% of the patients achieve negative cultures within 12 months. But it turns out that 94% of those had done so by six On the right are those who did not culture convert by 12 months and that was 24% of the group. But again, 93% of this group was also negative denied achieved culture negativity by six months. So whether you look at it from the positive predictive or the negative predictive side of this, It looks like what's happening in six months is highly predictive of what will happen at 12. So I think treatment refractory should be defined by not converting your culture. Uh it's six months. We shouldn't wait to 12. And what do we do with these patients? So this is a study called the converts study. This was a randomized control study of education, life with some inhalation, suspension or Alice plus guideline based therapy versus guideline based therapy alone in refractory Macaron disease. The figure here shows you the proportion of patients with negative freedom cultures for NTM If we start on the left at baseline, the darker bars of those who received Alice by one month, you can see that they were starting to separate. We're starting to see more cultural conversion in those who received Alice versus guideline based therapy alone And by month four is 30% vs nine. So that's highly statistically significant. Now this was amazing that this happened actually because to get into this study you had to be cultural positive for at least six months. But it turns out it was years for most patients. So this was a highly treated chronic and chronically infected population and they were able to convert and this was later shown to be a sustained conversion. So the micro biologic response was up to an M. I. C. Of about 64 or less. So we're seeing activity with fairly high M. I. C. S with inhaled like its own implications. So this resulted resulted in two new recommendations in the guideline in the first we said in patients with newly diagnosed pulmonary disease. We suggest neither inhaled indication of the parental formulation nor Alice be used. And we said this because there's literally not a single study that has looked at inhaled invocation of either formulation in treatment naive patients. Unfortunately, there are two studies occurring globally that are enrolling patients with treatment naive disease into a randomized study with Alice. The second point was in people who have MAC pulmonary disease who have failed therapy after at least six months. Again, that's the treatment refractory group we recommend in a highlight recommend because this is a strong recommendation. We recommend the addition of Alice to the treatment regimen. So this is a new recommendation based on what is now, you know an FDA approved product to treat treatment refractory disease. There are other things to consider when you have a patient who is not responding by six months was they always assess adherence would repeat drug susceptibility testing to make sure macro light resistance has not developed after on uh intermittent therapy. You can switch them to daily dozing. We showed in another study which I'm not reviewing that about 30% of people culture converts simply by doing that. And as I've already said, we would add Alice and I would consider probably absorbing their medications. You could check serum drug concentrations if they have cafeteria disease. Instead of Alice, I'd probably start intravenous embarkation and then eventually transition to uh to Alice. And of course I would add additional drugs if they're available. Now, the other reason we monitor is to monitor for adverse drug reactions. These are the drugs that we typically use in our treatment, naive patients and or refractory patients. These are the common adverse reactions you all know them. I won't go through them in detail just to highlight for macro lights really for us it's been gi symptoms are probably the most common issue. We do see some tinnitus occasionally hearing loss and of course it prolongs the qt. Thank you to all the main thing we're looking at and monitoring for is ocular toxicity for the rifle missions. Revamping as an example would be toxicity inside of penas education of course. Looking for vestibular and auto toxicity because we give this three times a week when we're giving it ivy we're not saying very much electrolyte disturbance or Nafo toxicity. And then with Alice of course 50% of patients will get Dysphonia and because it's a demeanor glucose side, they can get the same toxicities as the parental formulations. Now monitoring in terms of frequency and the guidelines we state that they should be individualized. The frequency should be based on the age of the patient comorbidities, concurrent drugs, overlapping drug toxicities and resources available. This is just an example of something you might consider. So monthly lab work speed, um culture, audio graham. I don't do lab work monthly but I know many colleagues do I do it more like every three months But we do recommend sputum culture be done every 1-2 months. Audio grams monthly for those receiving intravenous application for inhaled Emma cason and Alice. Uh We don't really know the best frequency to monitor audio grams. Obviously the the frequency of developing auto toxicity is much lower than with ivy. Um And again, this is something I would individualize kind of based on the their baseline audio graph every three months clinical monitoring, distributor testing eye exams for those on earth orbital and every six months. Things like low dose cT imaging like what we saw before and considering the CG. We didn't recommend that we've done and everyone. And again we would individualize that audio graham If you haven't done one earlier than I would do it now we we recommend reviewing airway clearance and our brackett's patients um at least every six months. It's amazing how quickly they fall off the wagon and we need to get them back on doing good airway clearance and then consider spi rama tree. Spectrometry does attract very well in our non cf patients. Um as it does with our cystic fibrosis patients. But for some patients you will see significant improvement. Now why is this important? Well it turns out adverse drug reactions are very common in the convert study over 90% of patients reported some adverse event in both arms. Um And we also know that adverse drug reactions can lead to some bad things like interruption and treatment morbidity for the patient in some cases not adherence because of the adverse event and even discontinuation of therapy. In fact it's been reported anywhere from 20 to 37% of patients discontinued therapy due to an adverse event. I would say in my practice, I don't see it that high. But these has been published Now, alterations of therapy can adversely impact treatment outcomes. In one study from Korea, 30% of patients who had a thon pathologist continued due to adverse reactions usually ocular um compared to 18% and those who continued with the hospital so to actually impact the their treatment outcome. So we don't want to stop drugs unnecessarily. And I think it's very important, particularly for the macro leads and a thank you to all that. We try to manage these side effects and keep the patient on those drugs. So are there any tricks to this trade? Well, I think really one of the most important thing is to just educate the patient about the possible side effects during that first visit. So there's no surprises. It's the surprises that gets people anxious and want to stop the drugs. Monitor for these side affection, manage them as soon as you can. Uh we often will temporarily hold medications whether the oral medications or inhaled Uh and then restart after 1-2 weeks. This has been, I think a very effective way to do this and it's amazing to be how often the side effect doesn't come back. We consider intermittent therapy for non cafeteria Nagvajara bracket. Tadic disease has been shown in a couple of studies to have a really very significant less side effects than the daily therapy. But again, you can only do that in non cafeteria disease and then we might switch out agents if they're not tolerating azithromycin. We might try clary vice versa, Maybe try retribution versus revamp in. So, you know, we were persistent in trying to find a regiment that the patient will tolerate. We found the dozing at night, particularly for those who have mild nausea is really good and can be the only thing you have to do to manage that. But in some cases we will have to use an anti medic if that approach doesn't work. So let me summarize NTM lung disease is increasing in many areas. The diagnosis requires the integration of the clinical radiographic and microbiological information. Um That is contained within that diagnostic criteria. Treatment consists of macro lead based regimen. We prefer azithromycin And this is administered 12 months beyond culture conversion. You can give it intermittently and those who have non cafeteria disease or daily and those who have cafeteria disease. We would also recommend I. V. M. A case in for 2 to 3 months in cafeteria disease. Once you start therapy you're going to monitor for sputum culture conversion because that will define the duration of therapy and also for clinical and radiographic improvement for Refractory disease. We now recommend that Alice be added and refractory disease again is defined as those who remain cultural positive after at least six months of therapy adverse reactions are common. So it's important to educate the patient, monitor them carefully so that you can make an early diagnosis and manage those side effects to keep the patient on therapy and hopefully improve the treatment outcomes. So with that I'd like to end and I like again thank you for your participation today Published December 23, 2021 Created by
