Hi, everybody. We're going to go ahead and get started. Thank you for being here for what is the 42nd Bowman Lectureship. I'm going to hand it over to Dr. Meg Keeley to talk about the Bowman recipients for this year. 

Thank you. It's good to see everyone I can see. And thank you for having us here at the 42nd Bowman Lecture, which is always hosted in Internal Medicine Grand Rounds. And we appreciate that opportunity. For some of you that come every year, just a refresher on why we're here honoring not only Dick Bowman but his memory through what is now what I think is the highest honor in the medical school, the Bowman Scholars and the Bowman Award. 

So to tell you a little bit about Dick who is pictured here, he was born in Stanton in 1945 and attended Hampden-Sydney in Farmville and majored in American history. He taught high school for two and a half years, and then he did some graduate work here at UVA before he entered the UVA School of Medicine in 1970. During the clinical portion of the curriculum he was particularly noted for his good nature, his maturity, his zeal-- I love that-- and his common sense, which really set him apart in dealing with patients and their complex problems. 

He was noted to have brought the theory and the practice of medicine together in a way which was exceptional for a young physician at any level of training. As a result his clinical performance was uniformly outstanding while he was here as a medical student. 

So while in medical school Dick met his wife Elizabeth as she was attending Sweet Briar College in Amherst, Virginia. They got married in 1974 in South Carolina. And Dick began a residency in internal medicine at Cornell at the New York Hospital in New York City. And his performance there, not surprisingly, as a clinician and a teacher won him the universal respect of his fellow physicians and his students, and the loyalty of his many, many patients for whom he provided care. 

As one of his colleagues in Manhattan observed, Dick was one of the nicest persons I have ever met, a joy to have around. Seldom have I met anyone who got such pleasure from life, who enjoyed his work so much, who balanced the conceptual and the practical so nicely. He seemed to embody all the best human qualities that make a good physician and a happy man. He was intelligent, kind, and had a keen interest in human problems. He had an unusual capacity of uncomplaining hard work. And his sense of responsibility toward those for whom he cared was never for a moment compromised by thoughts of self. 

So Dick and Elizabeth planned to return to Charlottesville in 1977 for him to start a fellowship in the Division of Infectious Disease here at UVA. But unfortunately Dick died in a sailing accident that May and was never able to return. His family, his friends, his colleagues, and his teachers turned really what was tragedy into what has become the highest honor awarded to medical students at the University of Virginia. 

We have a nomination process, where we have the clerkship directors nominate students who they think fulfill the qualities of what was outlined as the Bowman Award. Those qualities include the spirit and ideals of Dick Bowman, and were outlined as integrity; and uncompromising strength of character in his or her personal and professional life; enthusiasm for the acquisition and perfection of those skills which permit the physician to provide the best possible care for his or her patient; and a genuine compassion for the ill which complements a scientific approach to their unique problems regarding them first and foremost as persons in need of help. Finally, like Dr. Bowman the Bowman Scholars should be truly open, accessible, and approachable with diverse ranges of private interests and experiences. 

So every year the clerkship directors nominate sometimes as many as 45 to 50 students-- so a third of the class, which I think says something about the UVA of Medicine students. And somehow we narrow that down to 15 or so. And then somehow we narrow further down to the five Bowman Scholars. There are actually many former Bowman Scholars among the faculty here today. So I won't ask you to stand, but you are well represented. 

And so we recognize the Bowman Scholars at a dinner at the Rotunda, which we did several weeks ago earlier this month. And their families are there. Several of the former recipients of the Bowman Scholarship come. Some of the original founders and trustees and members of Dick Bowman's family also are there. So it's really an amazing experience. 

And we were pleased to honor the five Bowman Scholars who are joining us today. So I'd like to recognize all five of them. First-- and I'll just have them stand-- first is Meagan Briley. Meagan is from Greenville, North Carolina. And she went to NC State, where she majored in biology and history. And she is currently applying for residency in pediatrics. So congratulations to Meagan. 

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Next is Lois Davis. Lois is from Seat Pleasant, Maryland. She went to Cornell, where she majored in biology. And she is currently applying for residency in obstetrics and gynecology. To you, Lois. 

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Darian Hoagland who is from Flanders, New Jersey. She went to the University of Maryland at College Park and majored in physiology and neurobiology, and is applying as we speak in general surgery. Congratulations, Darian. 

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Jeff Ruland, who is from Portsmouth, Virginia. He attended the University of Virginia, where he majored in biology and Spanish. And he is applying for residency in orthopedic surgery. Congratulations, Jeff. 

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And as I said, we interview all five Bowman scholars the day after the dinner, which is an amazing experience and a privilege, really, to get to talk to all of them. And somehow, as dictated 42 years ago, we choose one person to receive a scholarship. And this year's recipient is Kristy Knapp. I'll have Kristy come up. She is from Newark, New Jersey. 

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She attended Ramapo College, where she majored in history-- much like Dick Bowman himself-- is applying for residency in general surgery. And so it is my pleasure to present the Bowman Award to Kristy Knapp. 

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So every year, as I said, we have a Bowman Lecture. It is always on the topic of infectious diseases, because that was what Dick loved and intended to study here or train in. And so this year we're very pleased to have Dr. Eric Houpt be our 42nd Bowman Lecturer. So I'm going to have your chief introduce him. Thank you. 

Thanks, Dr. Keeley. And congratulations to all the students, an outstanding honor to receive. I have the privilege to introduce Dr. Eric Houpt today. He's the Chief of Infectious Disease and the Jack M. Gwaltney, Jr. Professor of Infectious Disease. He got his MD from Emory, went on to the University of Chicago to do his internship and residency, and then came to Charlottesville to do his ID Fellowship at UVA. He quickly has climbed through the ranks within the division. He's been the Vice Chair for Research in the Department of Medicine, and now serving as Chief in 2015. 

He was awarded the Oswald Avery Award for Achievement in Infectious Disease, which is the highest honor of any mid-career investigator, and has NIH R01 funding in the area of Mycobacterium lung diseases. So please join me in welcoming Dr. Houpt as he gives the 42nd Bowman Lecture on Mycobacterium avium complex lung diseases. 

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Thank you, Sumner. Hope you can hear me. Congratulations to the five Bowman Scholar nominees. That's great. I certainly wouldn't have been one of the five. And it's a really lovely award. It's nice to see something last over the years like that. There's been a long tradition at Cornell and UVA, but particularly in infectious diseases. Jerry Mandell, who was the chief of the division for many years, came from Cornell. Mike Scheld, I think Erik Hewlett. And there's a number of others. 

And one of the fellows when I was a fellow, Dave Calfee, is up at Cornell now. He's coming in June to give our fellows' graduation talk. So there are some deep Cornell roots. And it's a tragedy that Dick couldn't be here. A lot of people come here and stay in ID, and he might have still been here. He would have been in Jerry Donowitz's class. 

So let's go on I'll talk about Mycobacterium avium complex lung disease. The title is more patients and multiple bacteria. I was going to talk about tuberculosis or enteric infections. But I decided to talk about this, because I think we see it as an increasing problem in the ID clinic. And I don't think we've covered this in a long time. So I thought it might be an interesting talk. I hope so for a number of you. 

I have no disclosures. I will do the standard epidemiology, clinical presentation, and talk about diagnosis and treatment, and then there's some research findings that I have at the end. 

So the epidemiology, we're talking about nontuberculous Mycobacterial lung disease. Medicare data shows that there's been an 8% increase in prevalence per year over about the last 10 or 15 years. So the amount of NTM lung disease is going up, such that now there's about 20,000 to 80,000 cases annually in the United States. It's still not a huge number compared with other entities, but there's about 9,000 tuberculosis cases. So domestically there is much more NTM lung disease. 

It has a female predominance which I'll talk about. And it's higher in certain geographies. And this has been known for a while. This is a map of Virginia. And in the '50s and '60s they did tuberculin skin testing of naval recruits, because there was a lot more TB then. And they did PPDT, which is TB, and they did PPDB, which is the [INAUDIBLE] bacillus, which is Mycobacterium intracellulare. And they used this to try to figure out, well, who actually has TB versus maybe the skin test reacted due to some environmental Mycobacteria. 

And you can see that's a map of Virginia. And it's cut off at the bottom, but sort of 30% to up to 70% of young male Virginians had been exposed based on skin test reactivity to Mycobacterium intracellulare. So these are environmental Mycobacteria. And you can kind of think of them as being all over the place, particularly in water and soil. And I'll talk about that later. 

But the southeast US has always been a hotspot for these. And so we see more of them than most other parts of the country. But there's other hotspots as well. 

If you just look at UVA, so I've done some work with Michael Hanley, who's a chest radiologist here. And if he just does a search for nontuberculous Mycobacteria in CT scan reports, you can see that over the past few years there's been more reporting consistent with, or consider, or whatever the verbiage is, of nontuberculous Mycobacteria in CT scan reports. This is obviously not the tightest data in the world. But it does show that it is coming up on the differential probably more. 

And the lower graph shows Mycobacterium infections at the clinical lab here at UVA from 2001 to 2008, when we looked carefully at what were the predominant Mycobacteria and what were the trends over time. And you can see more and more Mycobacteria are being isolated in the clinical lab. And red is Mycobacterium avium complex, which is the most common. 

And if you carry this forward out to 2016, which is the late last year that I have data, it's up to 142. So the amount of Mycobacterium and therefore, particularly Mycobacterium avium complex in the micro lab is going up. 

As for morbidity and mortality, and kind of how bad is this NTM lung disease, again using Medicare data and big data sets, there is some higher mortality in these patients than similarly aged patients that don't have NTM. Now, this could be confounded from comorbidities that many individuals that have NTM lung disease carry, such as lung disease is a risk factor. 

So it's not to say that these individuals are dying from NTM lung disease. It's likely that many sort of die with NTM lung disease, and there's other drivers of this somewhat increased mortality. It's especially high in males-- I'll mention that-- and in elderly, which is intuitive. And so I generally think of this as a slowly progressive infection with chronic symptoms and lung damage, particularly bronchiectasis. 

So there are two main clinical phenotypes that are worth keeping in mind. One is the male, usually a former smoker or current smoker, who has cavitary lung disease. This is a CT scan. You can see a large left upper lobe cavity with a thick wall, almost entirely destructive. This could certainly look like tuberculosis. You can see there's another lesion in the lower lobe on the left that was secondarily seeded from the primary upper lobe lesion. 

This man received therapy with azithromycin, ethambutol, rifampin-- these are the three drugs that we used to treat it-- for over a year. IV amikacin was also tried as well as clofazimine, which is more of an investigational drug. But he experienced ongoing disease, ongoing symptoms, worsening radiography. He was constantly smear and culture positive for Mycobacterium avium complex. 

He went for lobectomy, which showed caseating necrosis and abundant MAC. And that's what you see on the right, sort of this biofilm of a bunch of Mycobacterium avium complex organisms. And he died from the infection. And so despite trying all of the standard and even investigational antibiotic drugs, our treatment failed. Surgery was probably done too late. And this is a rarer phenotype than the next phenotype, but is really severe. 

So this is more common. This is a thin female that has nodular bronchiectasis-- sometimes just nodules, sometimes mostly bronchiectasis, often both nodules and bronchiectasis. So this is a 71-year-old female patient of mine. And she has had a cough for years prior to the diagnosis, persistent dyspnea. She pretty severe disease on chest imaging. You can appreciate some infiltrates bilaterally. There's also bronchiectasis in other areas of the lung. And her sputum has been persistently culture positive for Mycobacterium avium complex. 

So we've had her on therapy for years, including the standard triple therapy I mentioned, also IV amikacin. And she had some hearing loss with that, which is a bad side effect. We tried inhaled liposomal amikacin which I will mention. We've also tried clofazimine. But essentially, no improvement. So we're continuing her on treatment, but her disease really is not getting any better. It's just sort of kind of, I think, keeping it in check. 

This is her timeline since I've been seeing her for the last six years. She was actually going to come today to talk about her disease. But she couldn't make it at the last minute. And she's been on all of these antibiotics as you can see. You can see her MAC culture results are mostly positive. And her susceptibility testing, which I'll talk about, shows that she's still clarithromycin sensitive. So this isn't antibiotic resistance that is explaining her failure. It's just kind of a bad disease and very hard to eradicate. 

As for the susceptibility testing, only the clarithromycin result really matters. Maybe the amikacin result matters. Clarithromycin is the only drug where there's an in vitro, what you find on the susceptibility test, correlate with how the patient does in vivo. So we generally ignore the others on the panel. However, you will get this panel if you order it. And so you will have to know to mostly ignore everything else. But the clarithromycin result is important. 

And it means you can use the standard azithromycin or clarithromycin regimens. And clarithromycin resistance is fortunately quite rare. So of about 100 cases that we've seen here in recent years, there's only been one or two that have been clarithromycin resistant by susceptibility testing. 

So this clinical phenotype of the thin female with nodular bronchiectasis has been described for a long time. This shows the right middle lobe with some bronchiectasis. And some authors in 1992 said the following, that we offer the hypothesis that habitual voluntary suppression of cough may have led to the development of non-specific inflammatory processes in these poorly draining lung regions-- so the left lingula and the right middle lobe-- upon which MAC engrafted. And we offer the term "Lady Windermere's syndrome" to describe this pattern among elderly women and to suggest that their fastidiousness may be the root cause. 

Lady Windermere is the title of a play by Oscar Wilde and was sort of, I think, a very proper high society woman, who had very nice manners and would never cough. And so this is their hypothesis, is that women such as this with nice manners, and who don't cough, and would never cough because it's foul, may not clear their lungs from certain parts of the lung. And that allows the MAC to take hold there. 

This has never been proven, and many people entirely disagree with this sort of suppression of cough as the risk factor for why this demographic of the thin female develops often Mycobacterium avium complex lung disease. But that's where it came from. And I just mention it, because that's the story, and some people call this Lady Windermere's syndrome. 

But I think it's probably not true. I think what is true, though, is that these areas of the long-- the left lingula and the right middle lobe-- they do have long, narrow bronchi. They don't drain well naturally. They're vertical. And so I do think that, with this sort of exposure to environmental Mycobacteria, that it is hard for clearance to occur. And I think that is why it is seen most often in these individuals. So I do think there is something anatomic to those regions of the lung that is why we see the Mycobacterium there. 

I call this sort of phenotypes 2b, which is, again, the thin female with nodules or bronchiectasis, but one who has minimal or no symptoms. So unlike the patient I mentioned before, who is really suffering from chronic progressive infection, many people just have something like this-- maybe a nodule, maybe a tiny area bronchiectasis, and maybe no symptoms at all, maybe a little bit of cough. But that could be due to any number of things. And it's really hard to feel like the Mycobacterium avium complex is causing a lot of disease. 

Sometimes these individuals are identified because a CT scan is performed for other reasons. And if you look back, you can often see subtle changes for years prior, such that this has probably been ongoing for a number of years. Again, this is a chronic smoldering infection. Often such an individual is like [AUDIO OUT] this couldn't cough, wouldn't be able to produce sputum. And so they go for bronchoscopy or biopsy to evaluate for other causes, malignancy, and so forth. 

And very often the culture will be positive for MAC. And the question is, well, what do you do about that? Person's not really having symptoms, the CT scan was done for kind of other reasons, but all I've got is that there's MAC on the culture. Do I need to treat that? 

So that raises the question of, well, what do the guidelines say? What's the diagnosis of NTM lung disease? And, what's the treatment? So there are criteria from ATS, which is, person needs to have pulmonary symptoms and/or consistent imaging, such as this nodule. You need to exclude other diagnoses. And if you're going to diagnose it on sputum, you need two sputums. Or if they go for bronc, just one sputum would be sufficient. 

So this prior patient has consistent imaging, has excluded other diagnoses, went for bronchoscopy, and had Mycobacterium avium complex. So we would say yes, they make the diagnosis of having NTM lung disease. 

So if yes, the next question is, do you need to treat or not treat? And for someone with minimal symptoms you might just observe. And I'll explain why. And this is again what the guidelines say, is that one with minimal symptoms and radiographic findings such as the treatment seems worse than the disease, you can follow them closely, collecting respiratory specimens for AFB and follow-up radiographic studies, usually CT scans, over a long period of time, as the MAC will likely progress at some time, and the patient's symptoms will likely worsen. 

And I think this is true, is that that's kind of the natural history of this disease. And so you might just follow this person for symptoms, get a CT scan periodically. Now, that can amount to a lot of CT scans, so we get a low radiation dose CT scan, and you follow sputum for acid-fast bacilli. This is in someone who has minimal or no symptoms, but you think that they actually have MAC lung disease. 

If you're going to treat-- and this is for someone who has more than minimal symptoms-- then you're going to be signing up for at least 12 months. That's the treatment course. It's very long. It's even longer than TB. And it is usually 12 months after you document culture conversion. And we use azithromycin or clarithromycin. Consider them interchangeable. There's no evidence one is better than another. Plus we use rifampin. And this is regardless of the rifampin susceptibility result. Plus we use ethambutol, again regardless of the ethambutol susceptibility result. 

And you can use it three times a week for nodular bronchiectasis. That's been shown to be as effective as daily. However if there's cavitary disease, like the first patient I showed, then the guidelines are to use it daily, plus an IV amikacin. Now, this is only if the patient can tolerate it, because they're usually elderly patients, they have other comorbidities, that's a lot of drugs. These are not that well tolerated given daily. And now you're also adding IV amikacin for a few months. 

So the long-term efficacy is about 50%, I would say. Drug tolerability is an issue, and there's a high relapse or re-infection rate. 

So about relapse or re-infection. So it's known to occur in 15% to 50% of patients, and especially in those with the bronchiectatic form of disease. So here you see a normal bronchus, and then there's bronchiectasis, which is when there's destruction of the wall of the bronchus, there is loss of cilia, there is increased mucus. 

And you can imagine if you stick your Mycobacterium avium in there, because it's inhaled, and you don't have cilia to flush it out, and you have a lot of mucus, it will just kind of, the way I see it, stay in there as a biofilm. And it will be really hard to eradicate it. And so it doesn't surprise me that there is a lot of relapse. 

Molecular analysis of strains using pulsed-field gel has been done and historically shows that there is more re-infection, meaning you see a new strain. So a person first had A, and then you treat them. You treat them for 12 months or more, they're better, their symptoms are improved. You see them in follow-up. And two or three years later they start having symptoms again, and you culture them again, and you find MAC again. And you find that it's a different strain. 

So that is sort of historically held as the most common situation, is it's re-infection from the environment. Again, these Mycobacteria are everywhere, and they inhale another one, and it lands in this same bronchiectatic lung that was susceptible in the first place. And then about 20% relapse, where you find that it's exactly the same strain as was there before, such that you never really got rid of it. So that's the notion. 

So let's talk a little bit about the clinical microbiology of Mycobacteria, because this comes into play. So you collect a sputum from a patient, if they can produce it. And a lot of patients can't. Whereas, for TB they usually can. But for nontuberculous Mycobacterial lung disease, they often can't, in which case they often go for bronchoscopy. 

So you're going to send that for AFB smear and culture. The smear will be done within hours. It's basically just a slide on the microscope. If it's smear positive, you should know that you would probably want to order a molecular GeneXpert test to see if that is TB. If it's TB, you would initiate TB treatment with RIPE. 

If it's negative for TB, then it's likely MAC or some other nontuberculous Mycobacteria. And you should probably wait to treat. There's no hurry to jump on this 12-month treatment protocol that is only 50% or so effective. You may as well wait until you really know what you're up against. So that would be if the smear is positive. Most of the time it's negative, and you're waiting on cultures. 

So the cultures take up to eight weeks. And it's done on both liquid media and solid media. And the lab here stores all of the Mycobacteria cultures that are positive, because they know people may want susceptibilities later. So we have a bank of lots of Mycobacterium in the freezer. And when something grows, you have to, of course, identify it. Because all you know is there's some bacteria there. And some DNA probe is used to identify whether it's Mycobacterium avium complex or Mycobacterium tuberculosis. Those are the two main-- it could be a rapid grower as well, so there's other species that will be identified. 

But usually the probe is used to tell you which of these two it is. And like I said, most MAC lung disease is smear negative and is culture Positive 

Well, this probe just tells you that it's within this complex. And there's actually a whole lot of species within this Mycobacterium avium complex. They're pretty similar at the DNA level, which is why that DNA probe doesn't distinguish them. And it's generally thought that it's avium-- which you can see here is the most common-- or intracellulare. But there's a lot of other things in here that it could be. 

And so we did a study. It was 35 patients that met criteria for MAC lung disease. We had all of their isolates available, like I mentioned. So 95 isolates available from these patients collected over time, mostly patients with nodular bronchiectasis, because that's the most common form of the disease. Some individuals were off therapy being observed, because they weren't that sick. Some patients were on therapy, because they were sick, more sick. And some individuals in this time period had disease, were treated, and then had a relapse or a re-infection. 

And we wanted to see what species they had, because we've always assumed that it's, well, the same thing, but we didn't really know. And now there's a whole lot of whole genome sequencing available. And I won't get into all of the details. But just know that there's a lot of easy ways now to sequence DNA. And Mycobacterium avium complex has about five megabases. And for not that much money you can take an isolate and sequence the whole genome. And so that's what we did. 

And so we have 95 isolates from the patients that I mentioned. And you can see here that they're all listed vertically. There's a lot of different colors is what you're looking at. And you're seeing that there's a lot of blue, which means that those sequences that were sequenced from the isolates mapped to Mycobacterium avium. And so all those strains up at the top are essentially all or mostly avium. 

And then the middle orange is intracellulare. The green is Mycobacterium chimera. And then there's a mixture at the bottom with, really, various mixtures of different species, including some the other avium complex organisms that we never even really think about. And that's what sort of shown here, is avium and intracellulare and chimera and mixtures. And all of these patients met criteria for MAC lung disease. 

Prior studies of MAC lung disease have shown different things. So in Texas about 70% have been M. intracellulare. In Illinois about 25% have been chimera. And it's mostly avium in Japan and Korea. So we're a little bit like Texas and Illinois, I guess, which is maybe no surprise. But this level of resolution hasn't been looked at before. 

And so how about our patients? Well, like I said, our patients had multiple longitudinal isolates. So these are just their first isolates. And you can see that it's all over the place. And our hypothesis is that the patients that were not being treated because they had minimal disease, or those that were early on treatment would have the same strain. That's clinically what you assume when you send these cultures again and again, and you get MAC complex, MAC complex, MAC complex back. You're thinking, oh, well, of course they have MAC. It's the same infection over time. 

So that was the hypothesis. And that's kind of shown here, is a patient that-- the filled dot is their first strain, and then these are their sequential strains over the course of years. And they're all pretty much identical. They all map right here, and they're within 100 base pairs of each other. So these are really the same strain in this patient. So this is what we expected we would see for those patients. And by contrast we think those that had re-infection, because they're infection cleared, and they got a new infection, should have a distant strain. 

And what we found-- this is now lining up all of the patients in this section here, those that were off of treatment, those that were on treatment, and those that had clinical relapse-- is that there was just a lot of diversity in patients over time. So it was the exception and not the rule that an individual was coughing up the same strain again and again and again. 

And more often, a patient has maybe Mycobacterium avium, and then the next time we culture it it's intracellulare, and the next time it might be back to avium, or it might be mixed. So there is these long lines, because individuals are having all these different infections over time with different species or with predominantly different species. So that was quite perplexing, not what we expected. 

It has been mentioned in some older papers, again using earlier technology. So this is a patient from Texas. And they use pulsed-field gel. And they were followed over time. And you can see that some people have mixtures of A and B at the beginning, and then you find mostly A, and then it's back to A and B, and then it's mostly B. So this had been seen before, but not kind of with this level of resolution or in this number of patients. 

So some possible explanations for this is that MAC lung disease is often a polymicrobial infection. It's a biofilm. And there are shifts in this biofilm over time. Another explanation is that there's just different sampling from-- yes, it's mixed, and you get one isolate one time in your sputum because you happen to cough that up, and then another the next time you collect a sputum. Maybe there's different areas of the lung that are affected by different organisms. And it could be that there's just a really high re-infection rate from the environment in these susceptible Hosts. So if that's just happening all the time, you can imagine that you would see one thing one day and then a different infection the next. 

So this raises a lot more questions than answers. And some of the questions are, what is the clinical significance of a particular species? Is there one? Or, are we happy just calling it MAC complex, and we can just leave it there, and we don't need to know any more? That's just an unanswered question. Are certain species easier to treat? Are monomicrobial infections easier to treat than the mixed or sort of polymicrobial ones, or the ones that change over time? 

So this is going to take a lot more work to sort out. Let's talk a little bit about MAC in the environment and what's known about Mycobacterium avium complex in the environment. Because the environment seems to be important here. 

Joe Falkinham is at Virginia Tech. He's a microbiologist. And he's basically done all of the work on Mycobacterium avium and other nontuberculous Mycobacteria from the environment. He's cultured everything. He goes out and cultures soil, water, biofilms, patients, water heaters. And so he has a lot of experience in this area, and we've started collaborating on this project. 

When he's gone out and tested drinking water, he finds that about 15% have Mycobacterium avium complex in there. But it's mostly avium or chimera. You don't find intracellulare, for what it's worth, in drinking water very often. You do see intracellulare in the plumbing biofilms. It just isn't-- so it's in there in the plumbing. But it's not in the drinking water itself. So about 75% of plumbing biofilms will have intracellulare. 

And soil. So he's looked at potting soil in particular. Commercial potting soil samples, soil in individuals' plants at home. And you find about 100% have different Mycobacterium, which is shown here. And this is comparing patient isolates and soil isolates. And you can see that there's intracellulare, and there is intracellulare here. There is avium in the patient, there's avium here in the soil samples from those patients. And he's found a match in many instances. 

It hasn't been really rigorously done to know how tight this match is. It hasn't been done with whole genome sequencing so that you can really say, are these exactly the same strain. But he's done some initial work in this area. 

So some people recommend that people treat their water if you have MAC lung disease. And this is a list of things. What you can see is pretty significant. Drain and refill your hot water heater every two weeks. I don't even know how to do that. It sounds like a mess. Raise your hot water heater to 130 or above, because you find less Mycobacterium in the hot water heater when you do that. Remove and clean your shower head, because the shower head biofilm is filled with Mycobacterium avium complex. Get rid of humidifiers. 

So the three in yellow, I do tell my patients that they might want to do that. Because those are relatively easy to do. Whereas, I think if you do all of these things-- mind you, there's no data that says that if you do this your MAC will get better, or you won't get re-infected, or that your efficacy rate will go up for your treatment. So I think it's a lot to ask patients who may already be anxious to do all these things if it's not going to show any benefit, because you spend your whole life sort of paranoid of water and soil. 

But I do mention these few things to individuals, because they're simple. But more needs to be done here to really know if this makes a difference or this can help patients. 

Then we have a grant with Falkinham and Scott Heysell, and the clinical lab here, and the Virginia Department of Health that is supposed to start in a couple months, where we're going to collect these isolates and follow patients from all over the state. So Virginia is one of only a handful of states where laboratory reports for nontuberculous Mycobacteria are sent to the state. It's not a reportable disease the way tuberculosis is, but it is laboratory notifiable. So the lab reports go in to the state. 

And you can see that from 2013 to 2017, you know, they see on the order of up to 1,000 lab reports that are positive for some nontuberculous Mycobacteria. Some of these are going to be single positive things. Some of these going to be positive for nonpathogenic Mycobacteria. But if you drill into them, you can see that there's probably 300 or so individuals that have Mycobacterium avium complex in multiple specimens-- so the same individual multiple times-- such that they probably would meet criteria for lung disease. 

And a lot of them are in the eastern shore, which goes along with that very first slide, because there's a lot of exposure to intracellulare down on the eastern shore. So anyway, we're going to do environmental testing of all of these patients. And Joe is going to test water, and water biofilms, and soil from all of them. And we're going to do this whole genome sequencing to all of these different strains and try to understand how common acquisition appears from the environment, and how frequent it appears, and how often there is a match. 

And we're going to collect all of the case is over a multi-year time period to really see what the natural history is, and what the different species, how they affect outcome, and so forth. So it's going to be a lot of work to get this off the ground. But I think it will be important, since this disease seems to be going up. 

So in summary-- and then we can do some questions if there are-- MAC lung disease is a growing problem at UVA and in the US, particularly in thin, white, elderly women for reasons that are not completely clear. Most patients warrant treatment, but a few can be followed. It depends on symptoms, their radiography and microbiology, how persistently positive they are. 

Treatment is moderately effective. It'd be nice if it was better. But it's a long and difficult, and often not durable. MAC lung disease is not simply one infection. Speciation is probably important. I think that the micro lab is going to start speciating all of the MACs for this reason, just to kind of get a better handle on what's going on. 

And it appears to be polymicrobial infection and/or frequent environmental re-infection into a bronchiectatic lung which has poor clearance. And I really think of it as a biofilm type of disease. Sometimes you see fungus, sometimes you see Nocardia as well in these individuals. And I think it's reflecting the same thing. And we definitely need better treatments. 

There's one new drug approved in 2018-- liposomal inhaled amikacin-- for this. It got FDA approval for treatment refractory MAC lung disease. You give it daily. The endpoint of the trial was microbiological reduction over 12 weeks given daily, so for three months. And the primary endpoint was not achieved. So it did not microbiologically reduce MAC. 

But there was a greater proportion that had at least one negative sputum culture, and there was an improvement in a six-minute walk test. And this was enough to gain FDA approval. So not exactly exciting or that we're really thrilled at how effective this treatment is. But it shows how-- the reason this was approved is because there has been a lot of advocacy. This is an increasing problem, and patients want better treatments. And it went through a special pathway at the FDA for less common diseases, and treating AMR and resistant infections, and so forth. So they got approval 

It's associated with a lot of cough, which is not a very good side effect for this disease that causes cough to begin with. And a number of individuals had to stop treatment for side effects. But I do think it's good to have something else in the armamentarium. And I'd consider this in elderly individuals that we want to use IV amikacin, but we just don't want to risk hearing loss or kidney toxicity. So I think it will see some use. 

This is the last slide, sort of the life cycle of research I think you can consider. First you have to sort of describe the epidemiology of an important clinical problem. Then you want to, with that, apply new thinking and new research tools to the leading questions. And then ultimately, you want to get to an interventional study where you can intervene and test A versus B to see if you can improve the course of x disease. 

And unfortunately, for this I think we're way up top in terms of this understanding the epidemiology of this problem. We're trying to do some new research tools, but we're a long way away from knowing what are the best directions to go and to try to improve treatment for this. 

So thank you. Darwin Operario in the lab did the whole genome sequencing with the core here. Hardik Parikh did the bioinformatics with help from Amy and Mindy. And Scott Heysell and I see a lot of these MAC patients in the clinic. So with that, I'd be happy to take any questions. Thank you. 

[APPLAUSE] 

For those who have questions, just wait for a microphone. 

What a wonderful review. How do you tell when someone relapses or has a recurrent disease in these patients with long standing MAC? 

Well, it's usually defined as, patient has MAC, we treat them. We get them on treatment, their cultures become negative, they clinically respond. We treat them for 12 months, and then we just follow them. And we follow their sputum if they can produce it. We follow their CT scans. And then maybe two, three years later they start complaining of symptoms again. Sometimes they come in, and they say, I think the MAC is back. They produce a sputum, and we culture it, and the MAC is there again. 

[INAUDIBLE] 

So other than elderly white females, what are the determinants of susceptibility, given that these organisms are everywhere? And do you see them in immunocompromised patients? Do you see it in other folks? Why are only that group getting these and being affected? 

They're not the only group that gets it. So I mean, we see Mycobacterium and these infections sometimes in cystic fibrosis patients, other patients with bronchiectasis from any cause. That's a main risk factor. You see it sometimes in patients who have esophageal disorders, like achalasia. It's thought that there might be microaspiration from Mycobacterium in the environment. Obviously smokers, and pre-existing lung disease, and COPD is another risk factor. 

But you kind of put them all together, for whatever reason mostly who it turns out with these coming into the clinic is the thin elderly female. So that seems-- there's a lot of thin elderly female out there compared with cystic fibrosis patients. And so, you know, I don't think that's a very potent risk factor. But it's a very prevalent risk factor, and that's what leads to a lot of it. Yeah. 

That was just great. So one of the things that I wanted to ask you about is the other things that can affect the water-- so the disinfectants. So we know that monochloramine is great for Legionella reduction and elimination from the water. But it's also a great disruptor of biofilms and the microbacteria, they are not susceptible at all. And so when people switch to monochloramine as their disinfectant, it was suggested that it might increase microbacteria. 

And so when we moved to that methodology in Pittsburgh, we looked, and it didn't affect a change. But in other places it did. And so as you study the different areas, it would be one thing that you might consider looking at, is the disinfectant used. And in Virginia 70% of all Virginia is monochloraminized water. We're not monochloramine here in Charlottesville. But it could affect your findings of positivity of microbacteria. 

OK. Thank you. 

One quick question. As you indicated, it takes a whole year of treatment, and even then you cannot promise whether it will be effective or recurrent. I was wondering whether the problem might lie on whether these bacteria just colonized, or whether they're really infected, and whether you should do a biopsy before you put someone on this long prolonged treatment. Because if they are colonized, you're not going to get anywhere. 

Yeah. So it's a good question is, is whether these reflect colonization or disease. And I think the general consensus is that it is slowly progressive disease as opposed to colonization. I think if you follow these patients over a long period of time year after year, it will not go away radiographically. And the nodules will slowly get worse, and the bronchiectasis will slowly get worse-- slowly but worse. 

And so it's always a tough call is, how much do we think this is actually causing disease versus colonization? But my view is that most of it is just a slowly progressive disease, assuming that you're not finding any other explanation for it. 

As for a biopsy, you know, many of these patients get biopsies. They often get a needle biopsy of a nodule if you're looking for cancer, for instance. And you don't really get that much out of that. You get sometimes some cells, and they might see some granulomatous inflammation, that are culture positive for MAC. So you often do see granulomatous inflammation also suggesting that there's disease. 

But we don't really get sort of-- usually wedge sections or large lobectomies to really look in the airways to be able to say, well, how much of this do we think is colonization in the mucous layer versus invasion into the wall? But clinically it seems like it's mostly progressive disease, I think. Yeah. 

Yeah, the question is, is there any role for immunomodulators? You said hydroxychloroquine. I have no idea. I think, unless we get lucky with some really new antibiotic that works much better than the other ones, it's going to be an uphill battle of just treating this with antibiotics. I think that's right. 

You know, the macrolides-- clarithromycin, azithromycin-- were kind of a game changer though. They really improved the outcomes a great deal when they came along. So that's why that's like a critical drug to pay attention to. So we need a couple more drugs like that that are really, really good. But you know, who knows if anything is coming along. 

Even the newer drugs that have activity, like linezolid and clofazimine and bedaquiline, have been used for this. And it doesn't seem like they are game changing drugs. So I do think something else would be great, be it some immunomodulator therapy or anything like that. I just have no idea, you know, if or why it would work. 

I think so much of the disease is anatomic in a mucus layer, in a poorly draining part of the lung. And this is why surgery is actually considered a lot in individuals that have localized disease, like National Jewish, if you refer patients to them, they're basically a center. And they do a big workup, and they recommend a lot of surgery to remove the lung, or the section of the lung if it's localized. Most of our patients don't have localized disease. 

But there's such an anatomic effect that the question would be, how much can an immunomodulator really work for that as opposed to it being a primary immunologic failure. Yes. 

Eric, great talk. Any evidence that the amount of coughing in that FDA analysis was associated with improvement? 

The amount of coughing in which analysis? 

Well, with the inhaled amikacin. 

Oh. Yeah, I don't know. 

If you take clarithromycin and something that stimulates cough which ought to be in the control group. In any event, maybe Lady Windermere was right. 

I mean, the pulmonologist would know better than I. But I do think the chest physiotherapy, and the drainage mechanisms, and all of that are important to include in the therapies. I don't think they work that great by themselves. But they should be used. 

Dr. Houpt, thank you so much. Yeah. 

[APPLAUSE]