Hello everyone and welcome to e. r. s. 2022 in Barcelona Spain. I want to thank dr long for that kind introduction joining me. My name is Dave Griffith, a professor of medicine at national jewish health in Denver colorado. My presentation which is uh title clinical and microbiological confirmation of mac lung disease guiding antibiotic selection and intensity based on systematic micro biologic testing, risk stratification severity, score indices and prompt recognition of disease severity based on radiographic findings and patient comorbidities. Well ladies and gentlemen with that, I'm out of time so I'll be glad to take your questions. Well forgive me. That was a little bit of a lengthy title but now we will get into the meat of the presentation. I'd like to just start by saying for any clinician who manages patients with micro bacterial is the square one is having adequate support in the micro bacteriology laboratory. At a minimum you've got to have species and subspecies identification of clinically significant. NTM Iceland's. You've got to have appropriate and reliable in vitro susceptibility testing. We'll talk more about that in a minute and you've got to be able to do analysis of microbiological recurrences with more than one positive culture at a minimum. You've got to have species identification. Uh for instance avian versus intracellular charity versus chimera versus other mac species. And just as an example now mycobacterium avian complex which is the most common. NTM pathogen comprises 12 species and several subspecies. So if you are receiving reports and the organism is identified only as math. It's going to be challenging for interpreting microbiological occurrences. And I've got a great example of that coming up. But as I have said in talks for for some years now, the impetus for adequate laboratory support has to come from below. It has to come from us. We have to let the microbiologists and laboratory ins know what it is we need in order to manage these these patients. So first, this very quick review. I suspect everyone is quite familiar with this. There is a dichotomy in the clinical presentation of mac lung disease. The most common in the United States is not regular brachial static mac lung disease, generally occurring in postmenopausal females. Uh some with muscular skeletal disorders, usually low weight. Uh generally pre existing lung disease only with bronchitis is no other uh, pre existing problem. And also frequently with single CFTR mutations. This is a a long clinical course, patients are usually symptomatic for many years, prolonged cough fatigue is at least as common as cough and sometimes more bothersome. Uh The patient's sputum is frequently afb smear positive and culture positivity maybe broth, medium only or with countable colonies on solid media. It's important. They're therefore to collect multiple specimens from these patients before determining whether or not they have active disease. Um chest radiographs usually not adequate for a diagnosis and cT scans are required where bronchi ethicists and tree and but are not regular densities are are frequently seen. The middle open lingual are the most effective. And then fiber kava terry mac lung disease, which was really the only way this disease was recognized uh 30 40 years ago. Uh mostly men uh usually with preexisting COPD uh radiographic lee looks like tuberculosis but is generally not as rapidly progressive. Now these patients awfully often have afb smear positive specimens. And cultures are high yield again generally with broth and uh solid media radio graphically uh frequently this diagnosis can be made with chest radiographs but chest cT stands do illuminate other problems sometimes associated with these patients. In terms of NTM lung disease diagnosis. Um there really is not a major change in the 2020 diagnostic criteria compared with the 2007 document diagnosis is still based on the same three elements symptoms. Radiographic findings and microbiology. Microbiological criteria for both sputum and bronchoscopy have not changed at this point, I don't think can be overemphasized. The appropriateness of these diagnostic criteria is based on common NTM species uh that are recovered in a clinical setting such as mac obsesses, zenobia. There are close to 200 Michael bacterial, non tuberculosis mycobacterium species. And these diagnostic criteria probably don't fit the majority of those uh species. So when you get a rare or unusual. Uh micro bacterial species isolated in sputum. It's important to remember that these diagnostic criteria may not be appropriate for those patients. So should patients within p. m. pulmonary disease be treated with antimicrobial therapy or followed for evidence of progression. What has been termed watchful waiting. I have to admit that prior to the uh committee that uh has given us these 2020 guidelines, I was not familiar with the term watchful waiting. But in patients this is from the 2020 guidelines of 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 afb sputum smears or cava, terry lung disease. You see this is a conditional recommendation with very low certainty and estimates of effect. Well in truth, I don't think anyone follows that recommendation to the letter. I think most of us who manage these patients would agree that meeting diagnostic criteria does not automatically require initiation of any micro bacterial therapy due to the limitations of the diagnostic criteria. So for instance um NTM that are contaminants or unusual or rare respiratory pathogens like my Quebec term gordo near my Quebec term for to it. Um uh And Jordan in particular, if you have a patient that has multiple positive cultures for Gordana, you are still going to be skeptical about whether or not it's a true respiratory pathogen. Um and and as I mentioned of the Gosh 200 species, most are non variable. Uh and so you would be skeptical of uh pathogen. Perhaps you've never heard of, that is not described as a human pathogen. Even if you have several isolates of that particular species. Um you would again not necessarily begin therapy. And then there are patients who have MAC disease who need diagnostic criteria but we know or you have followed them and know that they have indolent or solely progressive disease. Now that's a risk benefit decision. And um as with all NTM treatment decisions uh requires input from the patients. Now in patients over 50% of patients who meet the diagnostic criteria for NTM lung disease are going to progress within 3-5 years. So these are some of the risk factors that are associated with these disease progression. As you can see uh male gender, older age, uh other comorbidities, low, low body mass index, uh elevated inflammatory indices like sedimentation rate and crp anemia, hypo album anemia and has already been uh expressed fiber cava, terry disease and patients with extensive disease. And then in the indicators of bacterial load like smear positivity and then NTM species to some degree. So for instance, mycobacterium perhaps michael back terms zul game um generally are associated with progressive disease. Mycobacterium dop um in several series is associated with increased mortality. So there are factors that help us determine which patients are going to progress. Now unfortunately we don't have a terrific biomarker yet. But many people are working on that. Um And hopefully sometime in the near future will have an easier way to do it. But right now this is all sort of empirical. So we have patients symptoms radiographic findings, uh culture results and then we have other factors that I just listed which help us try to determine who who is going to progress. I would also like to emphasize that watchful waiting is not really a passive process. Um Non disease, for instance is usually very indolent and fortunately there is time for appropriate data collection and doing a deliberate risk benefit assessment about the need for treatment. And every one of these patients just uh by name has another problem. They have bronchitis. So patients should be started on airway clearance for brock practices which can be transformative symptomatically. And a couple of studies have shown that there is a small but uh definite uh uh benefit for some patients in that the airway clearance per se will be associated with sputum, afb conversion. Uh And it's my belief that airway clearance is a necessary element for a successful antibiotic therapy of modular bronchial Caddick mac disease or other NTM Now there's not data that I can point to. That proves that point. It's just with experience patients who do not utilize airway clearance seem to have a more difficult time converting their sputum to negative. Um and it is important for the patient to engage with the managing uh physician because uh bronchi exegesis is a irreversible process. It's a chronic illness that requires chronic management and evaluation of the NTM status is something that uh is indefinite uh there is no sell by date for managing these patients. They will require uh surveillance and uh evaluation on a permanent basis. Now the management of these patients is I think the most confusing aspect of the micro bacterial disease. Uh Mac and other organisms. They demonstrate what's called innate or natural or cryptic drug resistance and that drug resistance is not readily or predictably associated with in vitro measures of resistance such as minimum inhibitory concentrations are M. I. C. S. And a great example of that is induce a ble macro allied resistance uh from the ERM gene for mycobacterium abscesses. And just very briefly uh several years ago when we would do in vitro susceptibility for macro lights in the standard way it would look like the isolate was microlight susceptible. We would treat the patient with macro light and nothing would nothing would happen. Well it turned out that there was this induce a ble resistance gene such that uh if you incubated the isolate in the presence of mackerel, I've you induce the gene you induced resistance and the M. I. C. Went very high for macro. So that that's just one very common example. And and actually it's one of the few that we have a good description for of how an M. I. C. Can look favorable but the organism can still be in devo resistance. So for a lot of these drugs for a lot of drugs for a lot of these bugs. In vitro susceptibility results such as the M. I. C. Don't reliably predict in vivo treatment response. So there are exceptions. So uh in vitro susceptibility tests for most drugs don't predict who will respond favorably or who will fail therapy. But for MAC there are two exceptions. That's the macro lied and um occasion. Where in vitro susceptibility results do reliably predict in vivo treatment response to antibiotics for mac lung disease. So where in detail susceptibility does correlate with clinical outcome. Clinically significant mutation of resistance can also occur without adequate companion drugs. So this process of resistance is similar to what we're familiar with with tuberculosis. This is not the cryptic resistance that I was just talking about. This is mutation of resistance that as I say, people are familiar with with Tv. So for mycobacterium avian complex, if you use monotherapy with macro lights, you will uh uncover uh Sorry. So if you use macro lights without companion drugs, you will select out resistant isolates with mutations in the 23 s ribosomes are an aging. Similarly, education without adequate companion drugs, you will select out isolates that are resistant as a result of 16 s ribosomes are in a gene mutations. So this is similar as I say, to what you would see if you gave I NH mono therapy for TB or monotherapy for tv. But I must emphasize these are the only two drugs from Math where you can select out isolates with mutations that confer resistance. So uh in terms of antimicrobial susceptibility testing for MAC. Uh the only uh two drugs that should be utilized for in vitro susceptibility testing are mackerel IEDs and claire with Armisen. Uh is the class drug for doing that and Emma cason. Uh None of the other drugs that we use for treating Mac infection have the same correlation between in vitro susceptibility and indigo response. Uh They frequently do have evidence of cryptic resistance but they don't have the mutation or resistance that you see with clarity remission and Emma case. So as you can see um there is a little bit of disparity in the allocation uh resistant M. I. C. Between intravenous, Emma cason and inhale uh Emma cason. And that essentially has to do with the fact that once the M. I. C. Is 60 for it is uh almost impossible uh to safely treat someone with intravenous A. Moccasin but you can still exceed that M. I. C. With inhaled uh like Osama land location. So these are the MAC treatment guidelines from the 2020 document uh for uh macro susceptible Mac pulmonary disease. Generally not like a three drug, Macro lead containing regimen is preferred uh is preferred over for tolerance reasons in general. Um And in with Nigel disease, three times weekly therapy is recommended over daily therapy largely because It's better tolerated. And there are data that efficacy is essentially the same with daily versus three times weekly therapy for patients with cafeteria disease Or far advanced severe bronchial, static uh disease or mac relied resistant disease, uh patients should receive um an intravenous or peripheral drug such as streptomycin in the initial treatment regimen for at least 2-3 months. Although the duration of treatment in my opinion should be guided by patient response. That is uh I would not arbitrarily stop at three months if the patient was doing well and tolerating medication without problems. Um also for patients with severe disease or Cavatelli disease. Uh Daily Therapy vs three times weekly therapy is also recommended. As you can see treatment success uh is varies between the disease type. There's pretty good data that for uh modular bronchial asthmatic disease, you can expect sputum conversion 80-85% of the time. There's less rigorous data for cavatelli disease, but it is apparent that it is a little uh sputum conversion is a little more elusive than for non modular disease. Now for MAC relied resistant disease. Uh and again, this is backed by at least a couple of studies unless there is prolonged intravenous or peripheral antibiotic use combined with surgery. That treatment success as indicated by sputum conversion um is very hard to obtain. Uh MAC relied resistant mag disease is an extremely difficult and sometimes fatal uh process. So we've just gone through this uh disease. Three times weekly therapy with metal for cafeteria disease. Daily therapy plus an intravenous antibiotic. Um And you uh you've just seen these data as well Now for there is a relatively new intervention for treatment refractory disease which is defined as positive sputum cultures for MAC after at least six months of guideline. Uh these therapy. This is a schematic of the uh phase two arms sorry phase three pivotal trial for inhaled liposome elam occasion uh given to patients who had refractory Mac lung disease compared to patients who continued just guideline based therapy without uh the inhale like Osama Obama cason. So um on the graph on the right um for the patients who received guideline based therapy plus um inhale liposomes casing at six months, 29% had sputum conversion versus 8.9% of patients who were only on guideline based therapy on the basis of this data. The Food and Drug Administration in the United States approved the use of inhaled liposomes. Education uh for patients with refractory uh Mac lung disease. And I should point out that it is the first drug approved by the FDA for any indication for MAC lung disease. None of the other drugs that we use including the macro lights have FDA approval for that indication. So from the guidelines, 2020 guidelines um estates and patients would make pulmonary disease who have failed therapy after at least six months of guideline-based therapy. We recommend the addition of inhaled cason to the treatment regimen rather than a standard oral regimen and it is a strong recommendation and I would point out again, it is the only strong recommendation in the treatment guidelines for uh MAC disease. Um in follow up studies, just as an aside the sputum conversion of the patients who took the inhale like education was strongly and significantly better uh maintained than the patients who had guideline based therapy alone. So the conversion was both sustainable and durable after while patients were on treatment and after they stopped treatment, it's extremely important to monitor patients for effectiveness while they're being treated for mac lung disease. Uh Different people have different regiments uh in terms of sputum collection. Uh My mantra is, there is no such thing as too much sputum uh collection in the laboratory. Um I generally get cultures at least month, our monthly until there is sputum conversion and then I I may cut back to every other month, imaging frequency is also uh there's not one way to do that. I try to minimize cT use uh and to order at pivotal moments in the care of the patient such as six months and that completion of therapy. But Again, there is not one approach to that. Um and treatment duration or treatment success is defined as 12 months of negative cultures while on therapy. I think it's also well recognized that patients frequently have microbiological recurrences after completing treatment. This is looking at three studies. When I was at the University of Texas Health Center. Tyler, we published a study where almost half of our patients within 3 to 4 years after completing therapy successfully had a microbiological occurrence. The big caveat to that is 75% of those recurrences were. New Gina types are new isolates, it was not a microbiological occurrence, was not a indicator of treatment failure or treatment relapse. As you can see. Our south korean colleagues had a little bit lower rate of micro microbiological occurrence, but the new gina types occurred at about the same uh frequency. Now macro lead resistance uh is a huge problem. We just don't have uh enough good medicines to give people with MAC disease if they become macro lead resistant. And this is looking at risk factors for macro allied resistance. We talked about Mac relied monotherapy, macro plus floral Quinn alone without other companion drugs is also a significant risk factor for uh macro wide resistance. And I would point out, I don't think the fluoroquinolones have any place in the management of MAC disease. Um And one other important point is that the most effective drug for protecting against macro light resistance is f and it'll even though it and it'll M. I. C. S. Are universally high. Uh And that protection of the macro light I think has nothing to do with the M. I. C. So if your laboratory tells you that the isolated is a little resistant, which they shouldn't do, they shouldn't be testing I think at all. Uh it would be a huge mistake to stop the beetle because the M. I. C. Is high metal is a critical factor in protecting the macro light. Um And as you can see mortality is uh not insignificant. Uh For these patients with MAC relied resistant disease therapy for macro lead resistant MAC there's no one approach but as I demonstrated earlier successes associated most often with the use of peripheral antibiotic and surgery in combination. Um Otherwise the speed um conversion rates are at best unpredictable but generally low. This is a slide I uh that I borrowed from my friend and colleague dr chuck daly. Which amplifies the point I made at the beginning of the talk which is about laboratory support. So this patient, as you can see uh at the beginning of treatment had MAC isolated from the sputum. But it but it was appreciated to Mycobacterium ADM. And the patient was put on and had initial sputum conversion with this regimen. But then a specimen came back culture positive from mycobacterium avia. But then uh to other species max species were isolated from the sputum. Now if all you knew or if your lab couldn't do speciation for you. Uh the these three isolates would all have been reported as MAC. Uh and they would have necessarily been interpreted as treatment failure. Uh We had another positive negative and then one more mycobacterium young tenants and then another negative. Now I will say interpreting this even with the species identification is not necessarily easy. But again, if all you had uh for the identification was met, this patient would clearly be identified as treatment failure. Surgery is an important adjunct. Um I will only say that that we use surgery for patients who are drug resistant or unresponsive to standard treatment with uncontrolled symptoms with him, opt assist or with areas of destroyed long with recurrent infections. I am fortunate to work with dr john Mitchell here in Denver who is the foremost surgeon in the United States for this type of surgery. Um there are no control studies that I'm aware of but uh for in a number of case series, patients who are eligible for surgery have better microbiological outcomes than those that are not now. You know, the problem is in the details when you start talking about who is eligible for surgery, what's the indication? What's the underlying disease for the patient? What's their cardiopulmonary reserve etcetera. But I do think it's pretty clear that for patients particularly who may have a large cavity or one area destroyed along with bronchitis is the removal of those areas facilitates conversion, dispute them to negative. And so I want to close with a quote from Manny Wolinsky uh this was from 1980 in his seminal American Thoracic Society. Uh review of the topic of NTM. So proper management requires greater expertise than is needed for treatment of tv first to decide who needs to be treated and second to determine which drug regimens to use. And I don't think anybody would argue that that's true. I would point out, sputum conversion rates for mac lung disease are maybe not even as good anymore as our conversion rates with MDR TB and certainly MAC relied resistant mac lung disease uh is at best comparable to treatment of XDR TB. We have a long way to go. Um These patients are present many management challenges, but I think uh we can we we can do okay um with just a little attention to detail and to the idiosyncrasies of the micro bacterial pathogens. I'd like to thank you all for your attention.
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