Video Applying New Trial-Based Evidence, Guidelines, and Individualized Approaches to Real World Management for MAC Lung Disease Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Applying New Trial-Based Evidence, Guidelines, and Individualized Approaches to Real World Management for MAC Lung Disease Overview CONTINUE TO TEST Back to Symposium Thank you very much, David. We're now moving forward, applying new trial based evidence guidelines and individual approaches to real world management of MEDLINE diseases. Let me ask you first. When would you test for NTM Pulmonary Disease? This was actually a question that was asked by a panel of international experts led by Professor Michael Lobinger from the UK, which uh resulted then in a manuscript that's currently in press among 455 survey experts from North America Europe and uh Southeast Asia Australia, New Zealand. They found that um those that physicians would consider te testing. Most are individuals with non cystic fibrosis bronchiectasis. That should really be the group where, where you should strongly consider testing other groups like in COPD or with the use of um immunosuppressants. Um those with frequently exacerbations with recurrent pneumonia. Uh And with CF they all by and large, only two thirds of the uh colleagues suggested that they should be regularly tested. But in those with non cystic fibrosis, bronchiectasis, uh around 90% and more suggested that they should be tested. And when it comes to um symptoms, those with persistent cough, also around 90% of those um experts that were asked would test individuals that have persistent cough for the presence of non tuberculous mycobacteria pulmonary disease. That's by far the largest group. Another group that also needs to be considered are, for example, those that have increased a purulent sputum. What would you consider actually for treatment initiation? Do you have a checklist? Like a pilot that starts a plane that you go through with every patient that uh you consider initiating treatment? We're actually suggesting such a checklist and that includes both the physician's decision to initiate treatment based on international recommended guidelines and also the patient decision and the readiness to initiate treatment. All caretakers that are involved in the patient care should be informed that treatment's going to start and counseling of adverse events and treatment monitoring should also be part of the information that the patient should get before treatment is initiated. There should also be counseling on cigarette smoking, discontinuation if that's applied to the patient, the baseline BMI should be recorded because that is a risk factor that can be corrected. There should also be in relation to the BMI counseling on the right nutrition, baseline imaging studies help to compare the imaging at the point in time of treatment initiation to those later when treatment should have resulted in a reduction of infiltrates or a reduction in cavities. Surgical options should also have been discussed prior to the initiation of treatment. There are also studies on treatable immuno deficiencies that should be performed prior to the initiation of therapy. It would really be a neglect if a patient is found out to have HIV infection. But that is only found out in the course of treatment and not at the time of treatment initiation because that is an immunodeficiency that is treatable, adjunctive therapy options should also be considered as well as mac drug susceptibility testing and also as a biomarker, the initial time to culture positivity. So the time it takes from putting the bacterium in the lab in culture until the culture system identifies growth of the bacterium should be recorded because that has implications for treatment outcome. And here we come to a biomarker. Is there a biomarker to predict treatment responses prior to treatment initiation? As I said, yes, there is, but it's really neglected. Almost no one uses it because the laboratories are not directly reporting the time to culture positivity. So you have to grab the telephone and call the laboratory and said, how long did it take for the bacterium to grow in culture until it was recognized that there is bacterial growth. Here. On the left side, you see a study that was published in chess 2022 that those who did not achieve culture conversion, read bars differed in the initial time to culture positivity to those in blue that achieved culture conversion. Similar here on the right side, those with a low time to culture positivity. In that study published in B MC ID in 2022 did not achieve culture conversion. Whereas those with a higher median um time to culture positivity prior to treatment initiation, achieved culture conversion. So the first time to culture conversion is really indicative of the chances to achieve cure with currently available therapies. There are also obstacles in the course of treatment and both the physician and the affected patients should be aware of these obstacles. What are they, there are adverse events that can occur with any of the medicines that are used? They could be um decrease hearing due to the azithromycin used. There could be um hepatotoxic due to the ror mycin used, they could be ocular uh or visual um decrease in visual accuracy. Um an optic neuritis due to Abit used physicians and the patients need to be aware of these adverse events. There could also be drug drug interactions, interactions, not only among the medicines that are used for the treatment of anti MPD but also with other medicines. For example HIV medication, if the patient is living with HIV, non adherence is really an issue in treatment of any chronic disease. So non adherence should be addressed also often patients achieve insufficient drug levels. So therapeutic drug monitoring should be employed to measure the drug levels and to adjust drug levels if needed. Also, there's a risk of non culture converging and if none, if the cultures do not convert at a point in time. For example, six months, the question should be raised if this is treatment, failure of this episode. And in addition, Paradoxic reactions could occur, so-called iris immune reconstitution, inflammatory syndrome that does not only occur in individuals with HIV infection but can also occur in non HIV infected persons. And this means that suddenly lymph nodes are swelling, that um pus collections are forming. And both again, physicians and patients need to be aware that that can happen. And that needs a prompted intervention. For example, the use of corticosteroids. How should physicians monitor treatment response? Are there any standards? This is interesting because according to the guidelines, monthly sputum cultures should be performed but many patients are unable to produce sputum and many physicians don't request those monthly sputum samples to monitor treatment responses. A simple diary like this one that is assessing patients self recorded body temperature, body weight, presence of night sweats, presence of cough during every hour of a 24 hour daily cycle. The sputum production, the sputum color, the presence of hemoptysis or fatigue. On a visual analog scale from 0 to 10 can be recorded in this type of diary and can be then handed over to the physicians at the end of a month who with a blink of the eye can identify if things are going well or if things are not going well because fatigue is increasing. There is fever episodes there is weight loss and other indications of therapy failure. So, when we balance decisions for treatment initiation, the pros to initiate treatment are the Wolinsky criteria that we discussed before. Like the presence of acid fast bacila on uh sputum smear microscopy, repeated isolate of the same speci species infection in an immunocompromised host or isolating from uh otherwise sterile compartment. But also the presence of more extensive disease like cavities or if there are limited other treatment options, watchful waiting may be advocated if there's minimal disease or no progression of disease over time, especially if the patient is not ready for treatment and doesn't consent. Or if there are really no treatment options to make things better like in a palliative setting. And in this regard, uh when the prognosis has to be valued or weighed against the quality of life, we're starting with a clinical case on the mac treatment pathway. This is a 67 year old female patient uh with a long-standing diagnosis of bronchiectasis who underwent right middle lobe lobectomy for hemoptysis. Her cultures had grown Aspergillus in the past and she's been treated for six months with hydro conazole but had no benefit in symptoms relief. She's now referred for recurrent bouts of hemoptysis with daily cough, productive of greenish sputum, no fever, night sweats, but she has weight loss and extreme fatigue. This is a section of her axial ct. You'll appreciate that there are cystic, not cystic, but there are bronchiectases. And there are these nodular lesions in the right lung and in the left lung. So this is nodular bronchiectatic disease. You may actually wonder if this is also a cavity over here which is too large of a um um cavitation of all this um proximity to the pleura. So unlikely to be bronchiectasis but still possible to be bronchiectasis and possibly be a cavity. Uh This would have to be viewed in another dimension as well but predominantly nodular bronchiectatic disease. In January, she presented with one smear positive an acid bacila seen on sputum smear microscopy in the following May with two on smear microscopy for acid-fast Basili and in October again with one and her Sputum culture in January May and October grew mycobacterial a complex. If we apply the 2020 A TS ES estimate and IDSA guidelines for the diagnosis of NTM Pulmonary Disease, we need the three different groups, clinical radiological and microbiological criteria. Clinical criteria. She does have cough and hemoptysis. She does have fever and weight loss. So she qualifies radiologically. She has nodular bronchiectatic disease. Perhaps that one cavity were we not so sure. And microbiology, yes, she has at least two sputum cultures positive for the same organism. In this case, mycobacterium avium complex. So all three different diagnostic criteria for NTM Pulmonary Disease are present. She had started airway clearance therapies with nebulized hypertonic saline and an oscillating post expiratory pressure device. She was empirically treated for gastroesophageal reflux disease and started now therapy for mac. According to the guidelines with Aromin 500 mg, hamutal 15 mg per body weight and rifampicin 300 mg daily. Um Milo, we have to make a quick cut here and I need to do this slide again and you need to please correct this slide also because it should read rifampicin 600 mg daily. 600. Ok. I'll make a note of that and correct that. So let's do this slide over again. I'll do the slide again. Ok. So she started um airway clearance therapy with nebulized hypertonic saline and an oscillating post expiratory pressure device. She was empirically treated for gastro oops reflux disease and she started antibiotic therapy for mycobacterium avium Complex disease with 500 mg of azithromycin with 15 mg per kilogram body rate of phenol and with 600 mg of rifAMPin daily. This according to the guideline for nodular bronchiectatic disease could also be offered three times weekly as per 2020 guidelines for cavitary disease. The same therapy uh is recommended but there's also the option to add IV aminoglycoside amicas or if drug susceptibility testing um shows susceptibility to Streptomycin as an alternative Streptomycin for daily therapy and also in refractory disease. The triple therapy of Azithromycin rifAMPin and EOL is recommended. In addition with Amicas liposomal inhalation suspension or with amicas IV, we prefer the am a case in liposomal inhalation suspension because of the much higher concentration that is achieved in the lung compartment, the less systemic adverse events, especially auto toxicity and to a lesser but important extent, also nephrotoxicity that um is a high risk on long term uh intravenous aminoglycoside therapy starting this treatment. Um December 2023 she for the first time had negative or undetectable acid-fast bacila on sputum smear microscopy. But as you see here on treatment January March and May, she again had positive detection of acid-fast bacila on sputum smear microscopy. And despite the treatment, she never achieved culture conversion. So in treatment on December, January March and May of 2004, there was always mycobacterium Avian complex cultured from the sputum and uh the cultured conversion can um be expected not in all of the patient success of cultured conversion is associated with macrolide susceptibility. Those who are unfortunate to are um falling ill with bacteria that have Merli resistance treatment success for eradication is really low. About 5 to 15%. Those with nodular bronchi aac disease. Like our patient have the best prognosis with about 80% of um culture conversion. And those with cavitary disease have a lesser beneficial um prognosis with less than 50% of patients achieving culture conversion. What needs to be considered in this patient is antimicrobial susceptibility testing to test for macrolite resistance. But also if you want to increase therapy for um aminoglycoside resistance, especially amicas, we also need to measure drug levels. Um under the broader term therapeutic drug monitoring to ensure that the patient gets the maximum benefit of high drug levels without causing um drug toxicity. And we also need to consider whether we are at an aminoglycoside to the therapy. A Amicas IV, which is recommended for CT disease per guideline or clofazimine um as um oral therapy and also to uh consider to give inha inhal therapy with amicas liposomal inhalation suspension. Um That is also according to the guidelines. Uh one of the options in uh refractory treatment, refractory disease and which as I mentioned earlier achieves much higher levels of drug concentrations at the site of infection than IV therapy without the systemic effect of auto toxicity and nephrotoxicity that uh is related to the administration of emy cason systemically. If we look at the penetration of um in native uh liposomal suspended amicas versus systemically applied amicas intravenously, we see that the concentration of amyas that is achieved in the alveolar macrophage pages is much, much higher with the liposomal suspended inhal form 274 versus 6.1. Um in the airways and in the lung tissue, the concentration is uh still much, much higher than um it is achieved with the intravenously administered form of amicas. However, uh intravenously administrated amicas achieves higher plasma level than the liposomal inal suspended nebulized uh inhaled form uh which again leads to much less systemic adverse events related with Amic casein, which are usually irreversible. So, overall parental. So uh intravenous amyas is associated with significant adverse events. Um overall in 37% auto toity um with um uh hearing loss and about 9% auto toxicity with equilibrium equilibrium loss and about 15% of patient experience renal insufficiency. So, our patient um was asked to reinforce a clearance therapies with the nebuli atonic saline oscillating pep device continued the G er D therapy and with the proton pump inhibitor uh received um Merli and Amy glycoside susceptibility testing and both were found to be susceptible. And in addition to Azithromycin buol and rifAMPin, she was then also offered amicas liposomal inhal suspended therapy. Those are 590 mg daily through a specialized inhalator device. We see from the uh convert study that in patients who fail therapy as um indicated by um positive mac culture at six months of treatment. Those who received Alice at that point in time uh onto the um background therapy with a macrolide, the button and uh ramp uh rifamycin. Um They, you see this here on the left side in the uh upper bar or upper line that the proportion of patients who achieved then culture conversion was much higher than those who remained on the standard therapy. Um On the right side, you see that 54% of those who uh started on a case in the uh suspended in native therapy that 54% of those achieved sustainable treatment success. Um Even 12 months after um therapy was uh finished. So, after initiation of um amicas liposomal um in a suspended therapy, the patient uh sputum smear converted in August uh to negative and uh remained negative throughout therapy. And she also achieved in September 2024 culture conversion and the mycobacterium avium complex cultures remained negative milo. Here is also something to note that um in the previous slide, you changed that already. But here you didn't change 2023 to 2024. OK, I will check. Yes, you're right. Yeah. So I in the text, I already um took the 2024 in in my my wording, but this needs to be changed in the on the left side. Yes, I will fix that. Thank you. Um So to summarize, how can we optimize the outcome in uh microti avium complex pulmonary Disease? First of all, to screen patients with risk factors, if we don't identify patients, we cannot optimize outcome because we just um have a natural outcome. This means that patients who have the highest risk and those are those with non cystic fibrosis and bronchiectasis should be screened. Also, you may consider to screen patients who had previously had an episode of tuberculosis, especially if they had cavitary tuberculosis disease. And you need to balance the decision about treatment carefully. And here a checklist will help uh to I before treatment is initiated, provide adequate treatment. Beware that the first hit is the best. Don't keep your magic bullet until the end but have the best treatment. Uh in the beginning of therapy, use antimicrobial biomarkers like the time to culture positivity as a predictor of disease severity and outcome in the beginning of therapy. And that may mean that you need to call the microbiology lab and ask them, how long did it take for the organism to be cultural? Then if you have limited options, consider antimicrobial intensification as the first step, not as an add-on step. There is old wording by Michael Aizenman from the National Jewish in Denver, Colorado never had a single drug to a failing regimen, monitor treatment and for treatment monitoring, you may use a um checklist like the one we've shown and expect obstacles and mitigate side effects alongside of the treatment. And with this, I thank you very much for attending the webinar and I wish all of you uh a very good day. Thank you very much for being with us. Published Created by Related Presenters Professor Christoph Lange, MD - Program Chair Medical Director/Clinical DirectorResearch Center BorstelBorstel, Germany
