So good morning everyone. Um thank you for being here and welcome the european respiratory society International Congress 2022. My name is Stephanie Liberty. I'm a professor of respiratory medicine at Humanitas University in Milan Italy. First of all, I would like to thank uh Professor David Griffith for his great presentation and for setting the scene on the microbiological confirmation of the N. T. N. P. D. And now I would like to talk a little bit about treatment guidelines um for patients with refractory and advanced Mark pulmonary disease. Um The objective of my presentation will be to review the guidelines recommendation for treatment of refractory advancement for Marie disease and to give and to share with you some real life insights in the management of this difficult to treat patients. These are the guidelines I was referring to. These are the 80 S. C. R. S. Asked me then I. D. S. A 2020 guidelines on the treatment of NTM P. D. Uh publishing clinical infection disease a couple of years ago. Uh These guidelines are pretty important for several reasons. First of all because uh both infection disease, physician and pulmonologist and patient representatives got together to discuss uh clinically relevant questions according to a great format. After 13 years from the previous uh 7 2080 s guidelines on NTM. Uh These are guidelines based on current evidence uh and are developed by four international societies to pulmonary societies from America and europe and to I. D. Societies from America and europe. Uh the way as we make the diagnosis of NTMP. D. according to the 2020 guidelines is pretty much the same. Uh that was suggesting suggested in the 27 in the 2007 guidelines. So we have three major domains. We have the clinical domain, we have the radiological domain and we have the microbiological domain. So if I have a patient with pulmonary or systemic symptoms consistent or for N. T. M. P. D. Plus a positive chest or chest X ray or CT scan with nodal or bronchial asthmatic disease, or cavatelli disease plus uh sputum culture positive for the same NTM species at least two times. Or one broker variola virus positive for NTM or biopsy in culture. Then these three domains together make the diagnosis of pulmonary disease. In the majority of the case, however, we should think we should have this very clear in mind that the treatment decision should be individualized for several reasons. So I agree. Uh and the majority of us tend to suggest the treatment of these three domains are present uh with these characteristics in the majority of the patients more we suggest more treatment than a watchful waiting approach, especially if we uh the cities can with the capitation or and if we have as mere positive. So in this case usually treatment is recommended more than a watchful waiting approach. However, we might have a patient with a very mild pulmonary or systems symptoms. We might have patients with no progression on cT scan and not cities can clear and consistent for N. T. M. P. D. Or patient with two sputum culture positive for an N. T. M. Or B. L. Positive for an NTM. But the N. T. M. Might be a colonizer, a contaminant, not pathogen. So in this case we suggest watchful waiting more than treatment. So there are plenty of plenty of items that we tend to evaluate in our patients when we discuss with the patient about wait and sea versus the treatment approach. So we we evaluate the pathogenesis city of the N. T. M. We evaluate the severity of the symptoms to think about severe fatigue or weight lost that are symptoms and signs that are very pro the initiation of treatment. We evaluate factor associated factors associated with a poor prognosis like gravitation. We evaluate the new system of our patients. We discuss with the patient risks and benefits of therapy. Usually patients are very clear with us in asking for potentials or the recurrence or infection or the percentage of cure for example. So we're together we evaluate her or his priorities with an ability to receive a very long treatment. We evaluate together the goals of therapy and all these. Usually take times take time. So we need to discuss maybe not just at the first visit but also during the second and the third visit the pro and counselor treatment rarely very rarely. We should start treatment for N. T. M. P. D. Immediately. So usually we have time to explain the disease to our patients and to discuss with our patient the pros and cons of the treatment. Um recently we perform um we try to investigate uh clinical features that are associated with treatment uh start in patients with NTM P. D. In. In Italy um asking uh physicians what were the major signing symptoms or scenarios that push us as a physician to start a discussion with our patients about treatment. And as you can see there are several variables that are interesting and I already mentioned this like the immune system, like people with HIV infections. Um the severity of symptoms like people with chronic productive cough or fever. Um of course there are some characteristics linked to the pathogen. There are some pathogens that we tend to treat more than other like Justice or Kansas city or canopy more than Jordan. Uh Of course there might be also the number of consecutive samples positive for NTM as an important factor that are driving our discussion with our patients. Um so this is a real life web survey that might inform our clinical community about what we are doing. As I mentioned in our daily clinical practice talking about pulmonary disease due to Mac mycobacterium maybe um complex the 80 S. C. R. S. Actually then I. D. S. A. 2020 guidelines are stratify ng uh the approaches according to the severity of the disease from a clinical and from an ideological point of view. So if we have a patient with mild moderate symptoms with inaugural bronchi tactic disease preferred drug regimen three times week weekly treatment without compromising or clarity. Amazing better victimizing, republishing or retribution plus a little while. If we have a severe disease from a clinical perspective and or a cavatelli disease then we move the dozing frequency from three times weekly to a daily approach with the three drugs plus application I. V. And usually guidelines suggest treatment for at least 12 months after cultural conversion. So cultural conversion is an important endpoint for for treatment. The other important thing of the 2020 guidelines is the definition of uh the refractory disease. This is a very new definition with important clinical and theoretical political um issues. First of all, the refractory disease is defined as a patient with remaining sputum culture positive for the same species after six months of guideline based therapy. And the reason why it's important to define a refractory disease and identifying people with Mac Pd. Refractory disease is because now we have evidence of a specific treatment for these patients. As suggested by the 22 20 guidelines, three drugs um itemizing revamp assing daily and on top we um guidelines are suggesting to have me casing liposome inhalation, suspension ellis as a treatment mainly because we have evidence for the use of this drug that by the way has been approved by both FDA and EMA. And is the only drug approved in Mark Pd so far for according to evidence published between 2018 and 2021 coming from the convert study. So the convert study aimed at evaluating both efficacy and safety of LS added to G. B. T. G. B. T. Is an acronym for guidelines based therapy in adults weigh the refractory mark pulmonary disease. So people that had an application susceptible market pulmonary disease with a market positive sputum cultures. Despite at least six months of stable G. B. T. These patients were randomized to 21 to receive either L. S. Plus or LGBT or oral GPT alone. So the gray bar, the great instagram for Ellis plus or LGBT. And the blue bar for the LGBT alone. Uh Ellis was supplied once daily. And the primary endpoint of the convert study was the cultural conversion uh defined as three consecutive monthly Mark negative sputum culture by month six. Uh So uh this is the reason why you see that we evaluate a month four because month four was the last time point At which a patient could achieve the first of the three negative student cultures in order to be considered a converter at month six and uh uh 224 patients have been enrolled in the convert study for the Alleys plus or LGBT group and 112 for the LGBT alone. These were mainly female median mean ager was around 64 65 years. So pretty much representative of what we are seeing in our clinical practice. Most of the patients that project this is um and the COPD as co morbidity. And the important message is that as you can see from from the figure um 29% of uh cultural conversion uh were achieved by patients enrolled in the Alice plus or LGBT group versus 8.9% of uh for patients that were enrolled in the or LGBT alone group. And this difference was statistically significant. Uh The other important point is um what happened at month 12? Uh there was a month 12 statistically significant difference between the two groups uh in terms of higher prevalence of converters in the Alice plus your LGBT group 18.3% versus 2.7% in the LGBT along group. The other study has been published by David Griffith with one of the speakers of the symposium in chest in 2021. This is a study with a specific research question. So the authors wanted to in Investigator in patients who achieved cultural conversion conversion at months six in the convert study. What happened after uh of treatment. Um they wanted to explore the if conversion was sustained. Um 12 months and was durable. Um So the data showed us that at month three we had 16% of patients in the Alice plus your LGBT group were converters versus zero in your LGBT along group. Um And at month 12 of treatment, 13.4% of patients in the Alice group were converters versus zero in the oral G. B. T. Alone. And these differences were statistically significant. We will take a look a little bit um the adverse events later on in my presentation. But I would like to um start looking at this study published by Kevin Winthrop in the Annals American Theological Society in 2021. This is a paper um This is a paper that I would like to discuss with you mainly from an adverse events perspective. So, adults with refractory Mark pd not achieving cultural conversion at six months. Uh from the combat study were enrolled in this 12 month open label extension Clinical Trial Waver. The aim of looking at safety. Tolerable Itty and also efficacy of Ellis plus G. B. T. People were 163 patients, 90 patients in the ellis naive cohort and 73 patients in the prior Alice court. Uh The clinical characteristics were pretty much the same that we are seeing in our we are expecting in our clinical practice in terms of um adverse events. As I mentioned, broken spasms. Uh Destiny A Withing uh were there both in the Alice knife court and in the prior Alice court um Auto toxicity necro necro toxicity and neuromuscular disorders were reported both in the Alice knife court and in the prior Alice court with these um percentages in terms of efficacy. The data were the data that we were expecting. According to the convert original publication, I would like I decided to show you this line because the concept of adverse events is very important for N. T. M. P. D. Patients. Okay, so the reason why I decided to talk about adverse events is because side effects are a real problem for N. T. M. P. D. Patients. This is a very important embark a L. F. Patient survey published by Michael Steinberg in 2021 in the european respiratory Journal of Research. So there was a very simple and clear question for R. N. T. M. P. D. Patients which aspects concerning management of NTM P. D. Posed a challenge for you. As you can see in the in the podium we have answers concerning treatment. So, first position was a long duration of treatment. Second uh worries over diagnosis and treatment of NTM P. D. But as you can see in the third position um the side effects of the drug was a very important concern uh for R. N. T. M. P. D. Patients. So looking at the convert study on the left part of my presentation And the in the 12-month open label extension clinical trial. In the right part of my of my slide you can see that the majority of the adverse events of Alice are respiratory including dysphonia caffe di Spagna and Amok assis uh that were present uh in in patients, patients in the palace group more rather than in patients in the G. B. T. Alone group. And this is reasonable because an email antibiotic was was added. So these were expected uh and uh tough task where they can be anticipated. These are the same adverse events that we know for from several several years for all the patients. I think we have 65 roses or with bronchitis is that we are treating with an inhale antibiotic. So we also have learned over the course of a couple of decades that there can be manageable with specific strategies. And this is what um Swenson and colleagues have looked at in this um in this paper published in the open forum of infection diseases in 2020 where people wonder went treatment with Alice have been investigated about adverse events. Uh Dysphonia increased sputum, increased cough and diarrhea, but also they were investigated also about the frequency of of uh these adverse events uh If uh these patients required management for these adverse events and what were the most common management strategies That these patients adopted and if they improved or not with this management. So starting with Dysphonia Dysphonia was reported as an adverse event in 73% of the patients who were investigated And the 68% of the patients required and management of Dysphonia. The strategies were mainly symptomatic strategies with the use of anti two saves um warm water or glycerin gargles or rinsing the mouth after nebulizer is use as we are doing in other populations, like in our 65 groceries patients for example. And uh the large majority of these patients improved. Um they're dysphonia with these specific management strategies In terms of increased sputum. This was an adverse events reported in 69% of the patient populations uh and 22% of these patients require the specific management strategies. Um the important thing is to be compliant with an appropriate area clearance technique. A former regime With these 75% of the patients improved in terms of sputum production a calf and dice mania and would add uh broncho constriction uh was was uh an adverse events reported in a 58 to 69% of the patient population. The majority of the patient required a specific management. In this. People adopted two strategies. The first one was to use a bronchodilator before receiving Alice. So this allowed me to go back to one of my previous slide highlighting the importance of recognizing and managing comorbidities in people with COPD and asthma for example. So we should be clear with the patient bronchodilator should be done properly. We we should check for compliance to bronchodilator therapy in these patients. And for those patients who are not receiving chronic bronchodilator therapy because they do not have COPD and asthma. Still, if they develop a calf broncho constriction and I spend the majority of us as physicians tend to prescribe bronchodilator before Alice and this will improve um these symptoms after the use of Alice. Sometimes we need to temporary adjust the dose so we tend to reduce um at least in terms of either those or frequency. Or rarely we should interrupt briefly the drug entry the patient accordingly. With these management strategies. Up to 90% of the patients uh improved in terms of despot nia and in broker constriction and allowed us to keep having them under ellis treatment. So management manageable. We have specific management strategies that we know since several years especially for people uh treated uh we have email antibiotics like those as I mentioned with 60 fibrosis and broke practices. There are several other crucial considerations in managing a refractory. Might be the first of all. We should always think that we need to look for potential environmental risk factors that we can manage. Um. Uh So we tend to ask about gardening for example and some of us uh There's no consensus but some physicians suggest that to manage gardening as a as a hobby for people with anti MPD we also are asked to check and to control underlining disease uh to be sure that these are optimized. First of all respiratory physiotherapy because we are dealing with in a antibiotic. So we want uh chest of our patients to be clear before uh taking the inhale antibiotic in. So we check for adequate respiratory physiotherapy. The majority of our N. T. M. P. D. Patients are uh bronchi static. So we need to look for compliance to treatment and for appropriateness of treatment of respiratory physiotherapy in these patients but not only respiratory physiotherapy. Also we need to be sure that all the other comorbidities in our patients are controlled um COPD and asthma if the patient is underlining COPD and asthma, gastroesophageal reflux disease for example for calf, if cough is one of our major signing symptoms uh for N. T. M. P. D. But also nutritional status. Um Some patients might might have a very low B. M. I. So it's important to give uh dietary advice or to send to a nutritionist um and several other comorbidities um among all the different ranks. Uh if uh my patient is taking email corticosteroids and there's no evidence that in l corticosteroids is important for my patient because my patient doesn't have asthma or a. B. P. A. Or important using a filic inflammatory airway inflammatory disease. So I tend to withdraw inhale corticosteroids because now we have solid evidence that inhale corticosteroids. Treatment is a risk factors for acquisition of a new N. T. M. These are the data from the embark NTM registry. Then there are several other considerations to be discussed with our patients first uh to understand if the bargain of treatment uh outwait the burden of disease If the patient actually is willing and able to receive enable antibiotic therapy. So we need to discuss this also from a practical point of view. Um And uh we always should think about surgery because if our patient as the criteria for surgery, it's important to discuss this option with her or with him. Um And finally I think that this is one of the most important questions uh that we all should answer ourselves as do we want to do this by ourselves or we need to refer this very difficult to manage patient to a specialist center. Uh I mentioned surgery and going back to the guidelines, the 2020 guidelines. They there is a conditional recommendation because based on very low certainty in estimates of the effect concerning surge that should be um suggested as an adjuvant to medical therapy in a selected patient in selected patients with anti MPD after expert consultation. So think about that. But this will undergo a multidisciplinary discussion in expert centers, the management of the refractory Mark Pd but also marketed in general. It's a story of trust. It's a story of trust between a physician and a patient in the context of the multidisciplinary t there are several several uh moments during, during the history of the disease. A diagnosis for treatment indication during follow up that patients and doctors um should discuss about goals about the strategies about compliance and I've learned over the past few years that a caregiver is crucial. Uh the identification of a caregiver is crucial to to manage patient with refractory market. D as a crucial is a multidisciplinary team where pulmonologist and infectious disease physicians are there to lead uh wide group of specialists including clinical microbiologist, pharmacist, uh psychologist, immunologist and radiologist but talking about in an antibiotics and nurses and respiratory physiotherapist are very very very important as important as telemedicine. Covid 19 strength, strength and our use of telemedicine for people with chronic respiratory disease. And this also is the case for people with MCS PD. And refractory Mark Pd because these are patients that we need to follow very very closely and maybe telemedicine uh is one of the tools that we are using as a physicians. And uh it's a tool used also by respiratory physiotherapist and finally patients association because these are very severe patients with an important psychological impact of the disease. So the patients should know that there are associations like N. T. M. R. I. Like the european lung foundation like a mantra which is the italian association of patients with NTM P. D. That can help the patient during this longer trip. So in terms of conclusions, um I think that we all should be aware of the fact that the treatment of a refractory or advanced Mark Pd is longer and very tough for the patients sometimes other than disease by by itself. This means that we need to discuss this with the patient and her is caregiver from the early stage of the disease, because the decision to go for a long treatment and difficult treatment with an inhaled antibiotic should be taken together. Uh The second conclusion is about adverse events. So I think that as I mentioned, family members, caregivers as as physicians or any health care professionals that are working uh to treat refractory Makati together with patient association, should be there for these patients. And then uh the third conclusion is about uh the importance of referral centers uh with the support from a multidisciplinary team uh that should be there for people with a refractory McVitie because of the difficulties in managing the disease and a long follow up and a very difficult journey. So with this I would I would like to thank you all for your attention and uh I would like also to introduce the next speakers speaker with Professor Christopher lang from from Germany, Thank you so much for your attention.