So, thank you so much, Professor Lange. Uh And uh my name is uh Stefana Liberty. I'm a Professor of Respiratory Medicine at to Manitas University. And uh um uh I would like to thank the organizers for the opportunity to talk about Mac PD and uh uh especially I will try to address in the next 15 minutes. Uh Some of uh some of the most important issues to me in the management of antimicrobial uh uh therapy in a patient with Mack Mack lung disease. First of all, uh I think we should um talk a little bit about outcomes of um patients uh uh with uh lung disease due to uh mycobacterium EUM complex because uh most of our thinking about treatment is mainly uh driven by the outcomes we want uh uh our patient um has. And uh if you take a look at the literature uh back in 2018, uh a large uh very respected uh group of uh experts from the NTM net uh community uh did a consensus uh uh process and published uh some definitions about treatment outcomes for patients with uh non tuberculosis mycobacterial Pulmonary disease. And the aim of this project was uh to enhance the quality and the interpretable of the results for future trials uh as well as retrospective court study. Uh And after the Delphi process, there was an agreement about almost 12 different uh MAC PD outcomes going from cultural conversion to microbiological and clinical cure. Uh from treatment, failure to recurrence, relapse, reinfection, but also mortality and treatment as you can uh very quickly uh see from the table on the left part of my slides, the definitions uh uh that the um NTM net group used are very precise. For example, cultural conversion findings of at least three consecutive negative mycobacterial culture from respiratory samples collected at least four weeks apart during anti mycobacterial treatment. So the question is how much these kind of definitions actually might be apply outside of clinical trials in real life. So we had the chance recently to review the data of uh patients with Mac PD enrolled in the Italian registry. Uh And these data have been presented in the war Bronchitis conference in Dundee. If key percentage of outcomes among 762 Mac PD patients, you see that cultural conversion is really low 24.1%. We were not able from the registry uh to have a good idea about microbiological cure or even cure. Uh while some other outcomes like mortality, uh we add the percentage of 5.6% or treatment to the percentage of 20.3%. So the major message from the secondary analysis of the Irene database is that uh in real life, we are missing precise standard operating procedures that can help in better identify MAC PD patients' outcomes according to the NTM net definition. So I think that this is extremely important because our patients want want a reliable and easy definition of their outcomes. When they ask us, uh can you cure my disease? Uh can I will be definitely cured by NTM Pulmonary Disease? So we need to think about outcome definition in clinical practice. So when we are starting a treatment, uh uh for uh a patient with MAC PD, uh we are mainly evaluating disease activity and the way as we start evaluating these activities through a clinical, a radiological and a microbiological evaluation. When we evaluate these three domains, we might also want not to propose a treatment to our patients and put the patient in what we call uh a watchful waiting. A watchful waiting means that the patient is not abandoned. The patient is still uh followed up uh with regular visit with a regular lung function test, microbiological results, optimization of respiratory physiotherapy, optimization of comorbidity. Uh But we do not propose our patient a treatment in the absence of the activity of the infection in the lung. But this is not just a question of disease activity. It's a question also of disease severity. It's a question of disease progression. It's a question of all factors and clinical relevance. So these four books at the bottom of my slides are representing the major questions that we are asking ourselves and our patients to propose or not propose a treatment. So we evaluate aging comorbidities, we evaluate possible drug to drug interaction or drug intolerance. We ask the patient, what are her or his wishes? We negotiate with the patient and name for the treatment. Then we consider not only disease progression, not only disease severity on time zero, but also disease progression from a longitudinal point of view. And then the kind of NTM species immunosuppression and several other aspects. So if I'm as in some key words that uh are uh popping up in my mind uh in front of a patient with a possible NT MP D I think about time. So usually I do not take this decision, this very important decision at the first visit, but I tend to look at the patient longitudinally across weeks or even months, multidisciplinary work because um immunosuppression, is there comorbidities uh is there? So we might want to ask uh our ent uh colleagues or our immunologists or our nutritionist or our psychologist to help us in managing the patient. Third keyword is keyword is caregiver because the journey usually is very long. So I want my patient not to be alone then clarity and transparency. And I think our patient as all the patients deserve clarity and transparency in addressing this important disease. And then I always have in mind that if I have a patient with NTM, this patient will be my patient for a possible infinitive period of time. So according to this consideration, I now want to address specific aspects of these four boxes that are bringing me to suggest or not suggest a specific intervention. First microbiology, as you can see, there are a lot of microbiology um issues in the tables and you know that the microbiology approach for mycobacteria in general is very complex. And uh if we do not consider basic and translational research, but if we are only focused on clinical research but mainly on diagnosis and treatment, you see that in the mycobacteria world, we are dealing with liquid culture with solid culture. We are dealing with the phenotypic drug susceptibility testing, but we are also dealing with CFU quantity morphology growth rate. So there are several aspects of the microbiology that should be considered when we decide to treat or not to treat a patient first of all species because we know this is a nice paper published by the European group that not all the species are sharing the same pathogenetic kind of burden. So for example, the mycobacterium Gordon usually uh is not treated while people with other mycobacteria like ab justus or even avium uh tend to be treated because of the pathogenicity of this kind of species. The second aspect is of course resistance, especially we are dealing with ma and diseases. So we are talking about maite resistance. And you see that uh the culture conversion rate is changing a according to the radiology aspect, cavity and not cavity. But you see how the culture conversion rate drops down from, let's say 50 to 80% uh to uh five or 15% in patient with a macro resistant. Then the mere positivity uh is another important uh aspect uh uh from the microbiological point of view. Uh This paper by one published in the uh E RJ back in 2007 identified this mere positivity as one of the most important predictors for MAC PD progression. But with an a ratio of 1.81. And then this other paper published in the Annals of American Tragic Society in 2022 identify uh people with a smear negative and smear positive having a different disease severity in terms of cavitation, bronchiectasis in terms of disease activity and in terms of time to treatment initiation. So smear positivity is something that we are looking at and finally time to positivity, time to positivity uh as an interesting literature uh uh in tuberculosis, but a recent literature in non tuberculosis mycobacteria. So I'm gonna uh use these three excellent papers uh published recently uh by different groups uh just to, first of all, to understand uh what uh the median time to positivity for an NTM might exist. Uh This is uh a retrospective experience from the Toronto Western Hospital. Back in 2015, 2019, 100 and 25 patients were evaluated and the median time to positivity was 12 days with a range from 6 to 44. And the time to positivity was associated with NTM disease disease activity, smear positivity and treatment initiation within three and six months. So this group used a cut off of 10 days to demonstrate that patients with a time to positivity, more than 10 days were associated with more disease activity, smear positivity and treatment initiation. Then I would like to talk a little bit about the secondary analysis from the converted data. Uh These are 71 patients where birth culture and TT P have been done in just one referral center lab in the roundabout uh center in uh Europe. And you can see that in this case, the median time to positivity screening was longer for patients who achieved cultural conversion in com comparison to those who did not achieve cultural conversion. So 10.5 days versus 4.2 days. And these show an impact on uh time to positivity on clinical outcomes. Time to positivity has been also evaluated in the third last paper, I want to cite in my presentation by Dano and colleagues in chess in 2012, uh showing an impact of time to positivity also on cultural conversion at different time points, the evaluation of the species resistance as mere positivity intend to positivity is also important during treatment or during the watchful waiting phase. For example, we should check the cultural negativity, spontaneous, cultural negativity on during treatment, cultural negativity uh or the appearance of a new non tuberculous mycobacteria or even the appearance of new bacteria fungi during the follow up. Similarly, smear positivity and time to positivity might change longitudinally in terms of uh increasing or decreasing and also resistances for different NTM might occur during treatment from a longitudinal point of view. So these four very important aspects of microbiology is not just should not be evaluated only for the decision to treat or not to treat but also during follow up. The other aspect of um the decision of treating or not treating the patient is looking at the radiological extension severity and longitudinal changes. We all know that we tend to stratify patients according to the nodal bronchitic versus fibro cavity disease because we have the data that are showing uh how fibro cavity patterns are associated with disease progression and how the number of involved lobes in MAC PD are associated with disease progression. And if you take a look at some scores that been published in literature about the association about disease severity from a radiological point of view in um in NTM, uh this song score has been one of the most cited taking into consideration project mucus plug bronchitis, the presence of cavities, the presence of noddles, consolidation, but also emphysema or mosaic perfusion. So different patterns giving different scores, different points for these uh scores. The song score has been uh showed to be correlated with some lung function data in this paper published in 2008. But now the literature is full about the use of artificial intelligence and deep learning based reduction model in respiratory diseases including NTM, pulmonary disease. LI and colleagues published in CHE in 22 in 2022. This very nice experience uh about an implementation of an algorithm to make a diagnosis of antia. And from a radiological point of view, when we're moving from morphology to function, maybe a pet cat is another radiological technique that might support physician in diagnosis, disease activity and especially looking at disease activity during watchful waiting or during a treatment stolen. And colleagues published this case series of 20 patients from terrain in Italy. Uh about uh uh the use of pet cat uh in patient with NTM lung disease. Usually the indication of a pet scan has been done accidentally because there was, for example, uh a consolidation or a no. So pet scan was prescribed um to exclude uh uh lung cancer. But then a diagnosis by maybe biopsy or bronchoscopy uh made that may was was an NT MP D. So pet cut was uh used during follow up. So this is another radiological technique that is extremely uh interesting for the next future. The last thing I want to talk about is um the radiology within the batch, batch uh batches is a, is a score able to predict mortality in NTM pulmon disease. And you see that cavity is one of the item of the score. This core uh can estimate the five year risk of mortality from 0 to 5, from um from 1.2% to 82.9% of mortality risk within five years. So, cavitation and radiology uh are part of a prediction model also for mortality. And finally, um uh the comorbidity and immunosuppression aspect. So, the host aspect is extremely important when we evaluated treatment versus watch for waiting. The Irey registry, the Italian Registry of Pulmonary tuberculous mycobacteria are showing are telling us that 89% of the patients in the registry as a pre existing lung disease, mainly bronchiectasis, 75% but 41% also have cardiovascular diseases and 27%. Uh they have at least one risk factors for immunosuppression. So, besides bronchiectasis gastroesophageal reflux disease, hypertension, active neoplastic disease, anxiety and depression, osteopenia, cod and asthma atrial fibrillation. Diabetes are all comorbidities uh that might have an impact on patients and symptoms and patient outcomes. According to that, you can easily understand how complex is the management of NT MP D patients that should not be only focused on antibiotic therapy, but should take into consideration. For example, respiratory uh physiotherapy and pulmonary rehabilitation because 75% of the patient might have bronchiectasis, uh also behavioral changes and health education. So, psychologists, psychiatrics, because adherence to treatment in a very long journey, journey is crucial. So 30% of the patient might be either depressed or anxious. So this should be identify as a treatable trait in NT MP D. And finally, nutritional evaluation, which is not just uh uh improving BM I, but also improving exercise, tolerance and muscles and muscles uh through the help of a nutritionist, for example, uh or dieticians, once we decide to start or not start treatment, we should have clearly in mind that the time for treatment initiation actually is important because there might be an impact for some patients on clinical outcomes. This study published by him in chest in 2022 evaluated 712 patients retrospectively among those who received more than six months of therapy because of an anti MP D diagnosis and they evaluated the timing of antibiotic initiation that was attending dependent. Uh And this patient might also have been put uh uh again, so sorry, a watchful waiting approach. So they found that 1st 67% of the patient converted within six months and that conversion within six months was associated with a reduced mortality. The adjust a ratio was 0.51. The median time to antibiotic was 4.8 months and the adopting a waiting period was not associated with cultural conversion of death. So a watchful waiting period for treatment initiation did not impact the survival of patients with NT MP D. However, achieving cultural conversion had a significant survival benefits. All these are important arguments that we need to clarify with our patients and we need to discuss across multiple visits with our patients. So to conclude, first of all, I think that a large consensus on standard operating procedures should be conducted that should be conducted after treatment initiation is needed. So we need to have a general agreement on when we should do a bronchoscopy, when we should prescribe chest X ray, when we should prescribe ct scan, because the presence of clear standard operating procedures and their results will help to better define outcomes in in real practice. So we also need after that a general agreement on outcomes definition in real life from a microbiological point of view, smear intent to positivity should be added in the microbiological report and should be interpreted also longitudinally because they are now coming out important data about the impact of for example, time to positivity on clinical outcomes, cultural conversion. For example, I mentioned something about artificial intelligence and the pet cat role in supporting the classical CT scan radiological evaluation. And finally, according to the importance of comorbidities as a treatable traits in NT MPD, the multidisciplinary approach is crucial to manage this aspect of the disease. So with this, I would like to thank you all and happy to get any questions you might have.
Related Presenters
