Video Optimizing Management of MAC Lung Disease with Guideline-Based Therapy Play Pause Volume Quality 960P 640P 512P Fullscreen Captions Transcript Chapters Slides Optimizing Management of MAC Lung Disease with Guideline-Based Therapy Overview Continue to Test Back to Symposium thank you dr longer for the kind introduction uh have the pleasure today to speak at this E. R. S. Uh satellite symposium on the role of bronchi axis and COPD as risk factors for mac lung disease Today. I'll be focusing on optimizing management of black lung disease. Looking to the current evidence based recommendations. What you see before you are two documents. These are where the guidelines were published. These were a multi society guidelines published in clinical infectious diseases as well as the european respiratory journal. These are My financial relationships. So let's begin with how we developed the guidelines. They were developed by a panel of 17 expert members. These were content experts to methodology. Ist one medical librarian from national jewish and one patient advocate. This is a very large field. So we had to scope these guidelines and really focus so we decided to focus on the most common manifestation of NTM disease and that's pulmonary disease in adults. We did not focus on HIV or other forms of immuno suppression or cystic fibrosis because they're actually other guidelines that address these. Then we had to take the approximately 200 species of NTM and scope those and focus down on the most common to cause pulmonary disease. So that was in medium complex in Kansas She and Xena Pie and obsesses today. We'll be focusing on mycobacterium avian complex or MAC. We use great methodology. We had 22 PICO questions in 31 resulting recommendations seven of which focused on back and we'll look at those today and unfortunately there's not a lot of high level evidence in this field, meaning we don't have a lot of randomized trials. So we were only able to come up with four strong recommendations. In those recommendations we use the word recommend. The rest are conditional and using great methodology. We use the term suggests before we treat probably the hardest decision is should you treat. So we tried to address this issue very early in the document and we call this watchful waiting, which means you're not going to treat with antimicrobial therapy. You certainly are going to treat their bronchi exorcists or other line underlying comorbidities. In this recommendation, we say in patients who meet the diagnostic criteria for anti um pulmonary disease. We suggest initiation of treatment rather than watchful waiting, especially in the context of positive afb smear or cavatelli lung disease. Now, if we think about the evidence to support this recommendation, we all know that there are factors both at the host level and the organism level that relate to progression of disease. I mean for example, we know that some NTM species are more pathogenic than others and we know that immuno compromised individuals are more likely to progress once infected. But studies have also been able to demonstrate there are other risk factors, things that are readily available to us as clinicians like the bacterial load and the radiographic extent of disease. These have both been associated with progressive disease. Other factors that have been associated and studies are older age, Low body mass index. Usually the cut point has been less than 18.5 comorbidities and some laboratory factors such as low albumin, anaemia and elevated inflammatory and disease. So this is kind of how I picture this this process. This balance between. Should you initiate treatment or proceed with watchful waiting? Well, you look at the species that they're infected with that may be one of the less virulent species and it may be in the setting of disease severity, in which there is no risk factors for progression. For example, non cava terry disease, afb smear negative and perhaps from the patient perspectives, they have a good quality of life and they have few symptoms. Now on the other side of this balance is that maybe they're infected with a more virulent anti um like my Quebec team Kansas city, they have multiple risk factors for progression and they have symptoms and poor quality of life. So we have to work on this scale to help our patients uh work through this decision process. Now. Once we decide to treat, we need to look at the laboratory for assistance and determining antimicrobial susceptibility testing. We pretty much followed the clc guidelines regarding this. If you look at the species here, these are the drugs that we recommend be tested in the laboratory. So for Kansas city, i it's a rifle mason, for MAC is macro light and a moccasin And for obsessive, also Mackerel it in education but also evaluating uh the earned 41 gene through either a molecular orphan a typical approach. Since we're going to focus on Mac today, let's look at these these recommendations. So these are the cut points for resistance for clarity, remission IBM Akesson and like the Somali moccasin. And you can see that there are different cut points depending on the formulation of a moccasin. So the cut point for resistance for the macro lives using chloroform ice and it's a class drug is 32 or greater for I. V. M. A case in 64 or greater and it increases up a dilution to greater than 1 28 for liposome uh formulation. So now let's think about how we might compose this mac regiment. What you see in the first column, basically an abbreviated PICO question. Our recommendations and then the evidence that supported that. So one of the first questions we asked was should you use a macro light containing regimen or a non macro like containing regimen here, we recommend use of a macro light and this is one of the few strong recommendations in the guideline. Now we made this strong recommendation despite the fact we had no well designed studies that address this, you know, no randomized trials. However, we have decades of data cohorts from different countries, showing always consistently that mackerel is susceptibility has been a strong predictor of treatments success. And on the flip side of this loss of the macro light is associated with a markedly reduced rate of speed um conversion Anywhere from 5 to 36%,, Much lower than the 80% that we expect was susceptible. Uh mackerel is susceptible disease. So if you're going to use a macro light based regimen and the next question was, which one would you use here? We suggest azithromycin over clareth remission. Again, we don't have randomized studies to help us with this. There is one occurring in France now but we do have equal culture conversion again from multiple cohort studies, no difference in macro light resistance and really the tiebreaker here is that the panel felt that the azithromycin was tolerated better. There were less drug interactions than with clareth remission. There's a lower pill burden and single daily doses. Well let's continue to think about building this regiment. So we asked the question, should you include an amino black aside in the regiment or no amino black society here we suggest use of a potential potential like aside for cava, terry disease, otherwise advanced severe bronchial Katic disease or macro light resistant disease. Here we did have one randomized trial from japan cited in the document which showed higher rate of culture conversion was streptomycin in a randomized placebo controlled trial than with a three drug regimen that did not include streptomycin. So we were able to find evidence of a back to recital effect of the amino black aside. We also have data from cohorts to show higher culture conversion and those who macro light resistant disease when an amino glucose it is included in the regiment. The caveat here is though most of those patients also underwent surgical resection. How many drugs will we administer here? Two versus three. We suggest a three drug regimen including the macro light. A thank you to all and rifle Meyssan over to drug regimen. Now, most of the studies that we evaluated looked at three drug regimens with very little data out there on two drug regimens. But there is one randomized study from japan. They did look at two versus three drugs and found the two drugs was non inferior to a three drug regimen in the intention to treat but not the per protocol analysis. This was an underpowered study. There were some method, a logic weaknesses and we did not feel that it was definitive enough to change our approach to treatment. However, it it was interesting and it has led to a very large study occurring at over 20 sites in the US and which were randomizing two versus three drugs for pulmonary MAC non cafeteria Mac. The expert panel was also concerned about the potential for acquired macro light resistance being hired with the two drugs but as I said, we do have a large study occurring and hopefully by the next guideline will have some randomized data to help inform this decision. So now let's administer the regimen. Would you give this as a daily regimen or an intermittent regimen, we suggest daily for cava terry disease in intermittent therapy for non cafeteria. Again, this is based on cohort studies that have demonstrated similar culture conversion rates with intermittent versus daily therapy pretty consistent across the studies show. They show that intermittent therapy has less adverse reactions and better completion rate than daily therapy and there's no increased risk of macro life resistance. However, there is very low conversion rate. If you give intermittent therapy to Cavite terry disease, that's why we have these two separate recommendations In terms of duration of therapy we kept with the 2007 recommendation of treating for 12 months beyond culture conversion. There are no randomized studies that have addressed this. So we really didn't have anything that would allow us to change that recommendation. And we do have some data from Cohort studies that have been looked at and systematic reviews. They show treatment success is higher in persons who have received 12 or more months of a macro lead based regiment compared to less than 12 months. Unfortunately, these did not look at time beyond time beyond culture conversion. They just looked at the the absolute duration but we think we're in the general realm of the appropriate duration. Probably the really only novel thing in the in the new guidelines. Uh is this idea of treatment refractory MAC. We define this as a patient remains culture positive after at least six months of guideline based therapy. So if you look in this figure, if we start on the left, we initiate treatment. We recommend in terms of monitoring for response that you do sputum cultures every month. This is very important because this again is how we define treatment. Refractory disease is also how we define the total duration by identifying when they convert. Let's take it out to six months and let's say in one case they have converted by six months, then we would continue guideline-based therapy for 12 months beyond conversion. If there's still culture positive six months, that is treatment refractory disease. And this is where we have a new recommendation to add a moccasin like for some inhalation, suspension or Alice to the regiment. So it turns out there are two recommendations that relate to in health education. The first we stated that in patients with newly diagnosed MAC pulmonary disease, we suggest neither inhaled indication of the potential formulation or Alice be used as part of the treatment regimen. That is simply because we have no data that has given inhaled evocation of either formulation to treatment naive patients has all been in refractory cases. There are two trials that are being conducted currently by uh instead that will be looking at the response in this population. So again for the next guideline will have uh some randomized data. But in the second this is where treatment of the refractory case comes comes in because in patients with pulmonary disease who have failed therapy after at least six months of guideline based therapy here, we do recommend edition of Alice. And this is one of those few strong recommendations and that's because it's based on very high level evidence and that includes two randomized studies. This is a figure from the publication by David Griffith. This is a converse study. This was a randomized control study of Allison treatment of Refractory Mac disease. That was a phase three study What you see here is a primary outcome which is the proportion of patients who culture converted by month four. So the darker bars of those who received Alice plus guideline based therapy, the lighter those who receive guideline based therapy alone. So you can see that as early as one month we start to see differences in the population with higher culture conversion rates than those who received Alice. And by four months it was approximately 30% of those who received Alice vs only about 9%. So if you continue the same thing you were doing after you determined that they were treatment refractory you get the same outcome which is very, very low rich culture conversion. So addition of Alice had a very significant impact on conversion in this refractory difficult to treat population. So we're left with really three approaches here based on the phenotype in a patient who has not regular Rocky Ecstatic disease. We recommend three drugs, macro lead based regimen azithromycin preferred. And you can administer this three times weekly for Cavett terry disease. We recommend that you consider 1/4 drug and that would be parental um moccasin or streptomycin here. We would give the regimen daily except you can give the amino black aside three times a week. We have this new category refractory disease in which we recommend four or more drugs. Uh In addition to guideline based therapy, you would add Alice. But if the patient still had cafeteria disease, you could also give parental um like 2 to 3 months of parental education. Uh Initially this would also be given daily except for the amino black to site. The final question was related to surgery. And this is what we recommend. And selected patients with anti employment very disease. We suggest surgical resection as an adjuvant to medical therapy. After expert consultation, We did a systematic review, we found 15 observational studies, including about 700 patients Who underwent surgical resection. And in three studies, including almost 300 patients that they were able to compare the outcomes of those who had surgery plus antimicrobial therapy versus antimicrobial therapy alone. The bottom line is that culture conversion was more common than those who underwent surgery, Complication rates were anywhere from 7 to 35%. The lowest was seven. That was here from the University of colorado. Um And that was a group that only had that surgery. Video assisted torque telescopic surgery, No operative mortality in any of these studies. Uh the postoperative mortality 0-9 again lower and those who have that surgery. But we do recognize the significant selection bias in terms of determining who should undergo surgery. And that's why we recommend expert consultation to make sure that the appropriate patients are moving towards surgical resection. So let me summarize so the diagnosis of inti um uh pulmonary lung disease requires a synthesis of clinical radiographic and my microbiological data. We now have studies are giving us an idea of the risk factors that are associated with progression and hopefully will help us determine whether we should progress with initiation of treatment or watchful waiting. We need our laboratory to help us identify the antimicrobial susceptibility results at least the microlight an indication A three drug macro like containing regimen is administered for 12 months beyond culture conversion. You can administer this three times a week for non cava terry disease. We recommend daily therapy in the setting of Cava Terry disease and also consider edition of intravenous application for the 1st 2-3 months which again can be administered three times a week. The new recommendation is to give Alice for treatment refractory Mac disease. Uh This is obviously a new recommendation. The guidelines and I know many clinicians may not have used Alice yet. Um Alice is clearly beneficial to our treatment. Refractory patients as with any new drug or formulation. there are side effects. Um I would say about half the patients will have some dysphonia, about a third cough. These are quite manageable. We often manage them by just doing a temporary withholding of the meds for a week or two and then reintroduced. And that seems to be quite effective. And then surgical resection is suggested for selected patients. Uh It's important to bring in experts who are used to doing surgery and these uh this particular patient population. So, thank you very much. I hope that uh I've been able to uh provide you with some useful clinical information that will help you in your practice. Thank you. Published August 27, 2021 Created by Related Presenters Charles Daley, MD Chief, Division of Mycobacterial and Respiratory InfectionsProfessor, Department of MedicineNational Jewish HealthDenver, Colorado, USA
