Presented by Michael F. Vaezi MD, PhD, MSc, FACG, Vanderbilt University Medical Center, Nashville, TN
Good morning. Thank you so much for joining me today to talk about me mucosal integrity testing. Uh, this is a new test uh that diagnosis reflux and is sending Felix esophagitis. But in order to talk about mucosal integrity testing, we need to know how it fits within the current armamentarium for reflux. And we also need to know what the limitations of what we're currently using are so that we know how best to utilize this device. So what I thought I would do is go over some just global clinical questions about when do we do diagnostic tests for reflux? Then talk about the current tests and what the limitations might be. And then bring in some of the studies that we and others have published on mucosal integrity testing and finished with an algorithm that I thought would be helpful in putting this test in perspective with others. I hope you will find this talk useful. More importantly, I hope you will be able to ask questions regarding any of the tests I talk about and me coastal integrity testing, its limitations, its strength and anything that might help you in better utilize diagnostic tests for reflux or use any filic esophagitis before I move on. However, I need to make sure we discuss disclosures. I know that I'm gonna be talking about off label use of P. T. I. Especially in Extra sant'Egidio reflux. I'll also be discussing off label dozing such as B. I. D. Dozing as you know, proton pump inhibitors are currently used at once daily and B. I. D. Dozing is off label indications for consulting you see the list there. But most important disclosure regarding this presentation is the fact that uh the M. I. Technology that I'm going to be talking about Vanderbilt where I work as a patent uh that is co owned by them as well as by divers attack. So I hope you will find the talk unbiased. But you need to know the disclosure that I've highlighted. Well let's talk about reflux as a whole, even though reflux sounds easy as far as diagnosed with and treatment, we all know that it's not so easy, especially in the era of E. P. I. Therapy. What do I mean by that? We often treat patients with reflux empirically and patients don't get better. Uh then what do we do? Right, so I'll talk about that in a minute. But when it comes to the Montreal classification for reflux, as you see on your left, its Asafa geo syndromes like typical reflux innovation that might present with heartburn, regurgitation, reflux chest pain syndrome. We know the association between uh esophageal motility disorder that also might result in chest pain. We also know the syndromes that have injury into the esophagus such as reflux esophagitis, or reflux induced esophageal strictures that might lead to patient having dysplasia, barrett's esophagus and ultimately the risk of adenocarcinoma, which is well known in patients with chronic reflux. The syndromes on the left are somewhat easier to handle than the syndromes on the right and that's the extra safi Jill syndrome. These are patients that present to us, not necessarily with the primary symptom of heartburn or regurgitation, but they actually present with call or laryngitis or worsening asthma, dental erosions, pulmonary fibrosis, or sinusitis, Recurrent otitis media, especially in the pediatrics, these have all been associated with reflux and because the presentation is somewhat quote a typical, they fall into the extra esophageal syndrome. Well, what is P. P. I. Try E. P. I. Trial is a way of diagnosing reflux and that is what we currently essentially employ a patient that presents to us with heartburn without any warning symptoms. We typically start patients on one's daily PP. I. Therapy and then we a sense response and then we start papering the medication. So the thing I want to mention about tapering of the medication even though that is our current recommendation that is start patients with PPE therapy if you suspect reflux. But we forget the second part. And to me that's the most important. And that is the tapering. Oftentimes patients are left on PPS which they may or may not need. But the only way to know whether someone needs chronic PP. I. Therapy versus chronic assets suppressive therapy that might equally be controlled with say H two receptor antagonists or lifestyle modification is to really taper the patients so start the patients on PPS than taper. So you're going to hear that message from me whether it be in this lecture or others that we need to taper patients to the lowest dose of assets suppressive therapy Now in those with extra esophageal reflux. The current recommendations start with the I. D. Dozing off label use and then paper the medication after a couple of months once you know whether the extra soft Ridgefield symptoms are reflux or they're not reflux related. So how good are pTS in treating reflux chronically? I think the key here is the Cronus City right? Oftentimes we're faced with patients that don't get better on PPS. But what we do know from this study, this was a study that looked at efficacy of PPS in this case Sa Metro ZOLL versus surgery, laparoscopic surgery. This is a european study and in this their first report that was published in gut after three years. What you see is that the efficacy of chronic P. P. I. In patients that have reflux is equivalent to surgery. To me the reason I wanted to show the slide wasn't necessarily compare the two. But to say that both therapies are pretty good when it comes to treating refund. They're highly efficacious. But the most important part of what I said is if you have reflux that is if you don't have reflux, obviously neither of these therapies will help. So the way we judge whether or not someone truly has the disease at times is based on their response to therapy and if they do have the disease ie reflux, then they will do well with proton pump inhibitor therapy. However, when what we're now faced with, as you well know from many publications and this is a summary that we published in 2017 looking at PP. I complications, some patients uh don't want to take their medication so they want to get off of the P. P. I. Or have surgery or endoscopic therapy. And these associations are wide range dementia, pneumonia, encephalopathy, anemia, uh spontaneous bacterial peritonitis, uh bacterial overgrowth. We are well aware of the funding gland polyps that are mostly benign uh the acute interstitial nephritis or chronic renal insufficiency and seat of colitis. Heart disease and dementia, which I mentioned. So the point is there are a variety of complications that are associated with P. P. I. U. S. I won't go into whether or not I believe these associations. And if you have questions I'm more than happy to discuss. I refer you to this publication in gastroenterology where we look at a few of these and critique them. But the point I make is no matter what patients do hear about these associations and then they come to us and say, are there alternatives? And in searching for alternative testing? I'm sorry treatment we do need to do testing for patients and those tests. I'm going to go over in a minute include testing for reflux disease with a variety of available technologies. And I call this slide come and get it because it's really a wide range of tests that we do. Right? So what do we have? We have ph testing that's catheter if you recall, if you're old enough. Uh The initial tests were these catheters that sat in the distal esophagus patients were these for 24 hours and we assessed whether they have reflux. We later added a second catheter that would measure um the electrodes being higher up in the esophagus measuring proximal assaulted deal or even higher in the hipaa fax. This had been the case since 19, late 1970s, early 1980s. And then later this was converted to the wireless as you see to the right. These are the wireless capsules also called Bravo Ph capsules where gets attached in the distal esophagus and we can measure the degree of reflux in this case 48 or up to 96 hours if one monitored. Uh Subsequently uh impedance ph testing came about, impedance. Ph was again a catheter system very similar to this. I'll show a picture of it in a minute where in addition to ph there were electrodes along the catheter that would measure weekly or non acid reflux. And uh the idea here was that if someone is on T. T. Therapy and they're still having symptoms, could it be that it's from weekly or non aesthetic reflux prior to the impedance. Around the same time we had this device called the bill itek. Again a catheter system where this well would collect liquid that is being reflux into the esophagus and through a cholera metric faction, it would measure the amount of billy Rubin as a surrogate marker for bio asset. So it would be a way of measuring whether someone is reflux in bile. The importance of that was obviously that on PP I perhaps again, patients are not reflecting asset, but perhaps their symptoms are from bile. As I mentioned, impedance ph essentially replaced this billet tech device with all of these three devices or four devices. Should I say? If you look at this tracing, what we measure is in this case asset and then with all of them, there is a way of patients pushing the button as these lines indicate to tell us whether or not they have association of their symptoms with those reflux events and you may be aware of reflux association, probability or symptom index and I'll talk about the limitations of that. This is a tracing with impedance ph which is this year later on, we had a oral foreign jal ph test. It's called the rest ph where the tip is actually in the oral pharynx. And this was set to measure reflux into the hypo pharynx and oral pharynx. And perhaps as a way of diagnosing someone that might have extra selfie geo disease. There was also discussion that during endoscopy one could biopsy and look at the dilation of inter cellular spaces as you can see here and by measuring them. Perhaps those would be early markers of reflux. And this is a pep then S a pap test if you will where a sample is placed in the well and the well uh similar to a pregnancy test, tells you whether there's peps in or not. These are salivary test. So uh it tells us if there's enough reflux that makes your saliva have Pepsi in it and that becomes a marker of reflux. No, these have been the tests that we've used predominantly these up here, I would say currently were either using the bravo PhD impedance ph or the catheter ph as the predominant means of diagnosing reflux disease. What are the indications for those tests? I already mentioned if you have someone that wants an alternative therapy. So, prior to anti reflux intervention, you do want to show objectively the patient has the disease and if they have incomplete or lack of response to therapy. In that scenario, we're really testing to see if the patient truly as reflux or is a symptom from something else. Going back to the technologies, it's important to know that these technologies are kind of old, most of them. So, ph testing, ambulatory ph came about in the late seventies and in the eighties and then we had the wireless ph in the early 2000 and then impedance, ph and breast tech was also in the two thousands. And then what I'm going to talk about, which is a mucosal integrity uh put in here 2016 or 17 where the public the first publication was. But really this is now FDA approved and that would be 2020. So this is the newer diagnostic tests relative to all the ones that we're currently using or have been exposed to the word about Ben and now. Um the way we diagnose reflux then and the way we diagnose reflux now and the implication of sub optimal therapy versus and Peric therapy. What do I mean by that? In the 19 early 80s, I'm sorry or early 90s, Our therapies were either sucrose fate or H2 receptor antagonists. So clearly suboptimal and in that group of patients we would test them and we would often find esophagitis or abnormal, th this has now changed. We are now in the emp eric therapy mode and that we treat patients with once daily PPE then twice daily and then we test them. We test them if they have continued something. So the question becomes, what is the pretest probability of someone back then having reflux? If they didn't get better? I would say much higher Then. Now on DVD dozing, when they're not improved, the likelihood is less as we all know because when we do endoscopy most of these patients are normal. When we do ambulatory testing, many of them are normal or have only mild abnormality, which would not explain their symptom. So to put that another way that's no therapy reflux. You treat them with one stately therapy. And if someone truly has most of them uh become a symptomatic. And the ones that continue to have symptoms shown in yellow is a smaller population. And then of those that are still symptomatic on B. I. D. Dozing, the likelihood of reflux is reduced yet. So what what I'm trying to show here is that the pretest probability of disease is really much lower and nowadays than it was back then. So we have to keep that in mind then why do we do diagnostic tests? We do it to show someone doesn't have the disease most of the time or if they do it's mild or if they do have the disease, we're doing it fire to anti reflux interventions such as endoscopic therapy or surgical funding application. So remember that. So let's talk about these tests. I showed this slide earlier and I also mentioned that These there are many of them are either catheter based 24 hours or 48-96 hours. I call them short term data. What do I mean by that? We place a catheter or a capsule and we measure acidity, usually for ph measurement or with impedance, ph acidity plus changes in impedance for non asset in a very short time period. And then we say someone has the disease or don't. Well, that's so excited when we look endoscopic lee at someone that has had esophagitis. The reason we accept the esophagitis as a measure of disease is because of the Cronus city of reflux that is led to the epithelial erosion, which is now obvious. So that Chronis City is manifested by erosions in the esophagus. These tests are very short term, one day or two day or three or 4 at most. And guess what? As we all know, there's high degree of variability. We also know that it's dependent on patients actually eating what they normally eat with catheter system. It's exceedingly difficult. We know that there's a 30% false negative rate with catheter ph test when it comes to reflux because patients actually older what they do when the catheter is in the system with the capsule, that's better. But even there there is variability. And also remember, most patients will have normative data and when we do find abnormality, it's going to be mild to moderate at best. Most people won't have much because they've already tried twice daily therapy and that failed. So, these are very short term studies. Let's talk about another way. Uh, they have limitation. Well, think about it. Where do we put the capsule six centimeter above the square. More kilometers. Why not? Seven? Why not? For Why not? 51 I three. Where do we put the PHR impedance? Five centimeters above the mana metric? Ellie yes. Why? Right. You could ask. Uh And if you ask that question by standard by normalization. So these are systems that are placed at a specific point and abnormality at that point defines the disease. Rather than looking at the epithelium and say, well there's no esophagitis. But is there a marker of disease? Can we use another marker? Such as alteration in the epithelium? The dilation of the cells? Well, we can't biopsy it because you don't know where the biopsy, that's where mucosal integrity comes in. And I'm going to show you that with this device, you're actually sampling a large portion of the epithelium. And the sampling allows us to know whether there's been alteration on the epithelium as a consequence of reflux. So it measures cruel necessity of the disease rather than with these short term data collecting devices. So where did the concept of mucosal integrity come from? It was really from this, I was writing an article and we were talking about how this is a if you if you do these tests, this is an impedance ph this is the catheter system, this is the ph part and this is the impedance part. This still esophagus and then you go proximal. One of the things we used to tell people is that you cannot use impedance ph data and someone that has these two diseases adopted guidance or barrettes. The reason for that is that the baseline is much lower in patients that have new coastal changes i. E. They have truly reflux disease. So that occurred to me. So why couldn't we use that baseline as a marker of disease? You've probably heard some people have used the nocturnal uh mucosal uh impedance as a way of measuring reflux or what they tend to do is use the baseline here as a way of assessing whether there is reflux. The problem here is just look at just one patient. Look at the baseline impedance in the same patient at one night, at different location. Look at the variability and I'm going to show you another side. Look at the variability. Look at the variability. So it creates variability. If one uses this data as a way of assessing whether or not there's alteration. But also you have a catheter in someone's nose. Nikko cell integrity is done during endoscopy patients sleep. You do it during endoscopy may take an extra minute or so and you're done and then the patient doesn't have to be monitored chronically have a catheter in the system have to come back dropping the monitor off. So all of those are benefits. And there's the more accuracy of the data collection rather than arbitrary deciding well, I'm going to pick one a.m. As my target and then I'm gonna average all of these measurements. You could do it but your measurement will not be as accurate and I'll show you that. So that's where the concept started. We initially started with a catheter system that had two impedance electrodes at the tip. These are three millimeter sensors with two millimeter separation. And you may ask, how is that different from the intra Luminal one? This is the concept that we used for mucosal integrity and this is the Luminal impedance ph monitoring. You can see the much larger sensors, much larger separation and also as I will show you, much larger variability on your estimate because at the end of the day you want your estimate of the measurement you're taking to be as accurate as possible. This will not allow it to happen. If you use that with that proof of concept catheter that we have created through the working channel of the endoscope, we would actually put the sensors against the mucosa and then take measurements. Here's a picture of that. And we were taking measurements along the epithelium and when we did that we found several interesting findings. We had five groups patients with eosinophilic esophagitis, those with esophagitis, those that had normal endoscopy, but abnormal ph So these are the reflux patients. And then we have those that had normal endoscopy normal ph and we use their cool asia as a second control if you will disease control, you may ask why that Malaysia a control group and if you do, I'm happy to go over that in the Q. And A. But essentially the mucosa, nickel asia is more intact. And the reason during intra Luminal catheter, you see a drop in impedance is because of the liquid that collects an equal asia patient if you're able to touch the epithelium that's actually intact. So that's another reason you don't want to use the intra Luminal Catherine. So what we saw was an interesting pattern And we published us in 2015. And what you see is that in patients with eosinophilic esophagitis at the bottom a few centimetres above the squamous columnar junction. The impedance measurement is low, suggesting alteration and epithelium which stays low all along the esophagus. When you come proximity, that makes sense. Patients with the O. E. Have alteration and the epithelium that covers the entire span of the esophagus. In patients with reflux where reflux happens more distantly initially. What we do see is alterations in the distal esophagus which then recovers as we come approximately And in those that are the control groups we see intact epithelium that stays essentially within the norm of the mucosal integrity being above about 2500. No, they're patterns someone can identify. Low. Am I at distal esophagus that the slope stays low, Lower mind the distal esophagus where there is a slope, increasing slope, that's your reflux and high. Am I at distal esophagus which essentially stays high? Now I wanted to do is go over this intra Luminal impedance difference versus in mind because this keeps coming up at various meetings. So here's the estimate essentially what I showed you. This is the mind mucosal integrity. You notice how tight the data are and here is the same individual and you're trying to find where the accurate data is here. Right? So look at the spread of the data and the variability versus that for am I That makes it tough. What is your accurate estimate? So the accuracy suffers and you have a catheter in someone's nose? All right. We then said, well, we don't want to just measure one small area in the esophagus. Can we have sensors all along the esophagus and see if we could measure what's happening in the epithelium. The problem with that is we didn't want to do it similar to intra Luminal. We wanted these sensors opposed and we wanted to ensure they were opposed. So what we next It was actually put a balloon over that catheter and then took measurements that reduced interference from liquid and air on this part of the sensor. And it made sure that the sensors opposed the epithelium so we could get accurate data again, this is a proof of concept study and that led to placing the sensors. You see these flat sensors along a balloon so now we can actually introduce the balloon from through the oral pairings. And we have the measurement from the distal esophagus to proximal. We usually place this at two cm above the squamous columnar junction and then take measurements. What's nice about it is you inflate the sensors oppose the epithelium and you have your measurement The initial balloon. We have four strips of 10 centers. Here's one, Here's to underneath is the third and then on the other side the fold. So we were taking 40 measurements Along the Esophagus, 10 cm long and this was every 90°.. We wanted to see whether that made a difference, having four sensors or two sensors. And later on we found out that you don't really need all four sensors. That two sensors, 180° apart was sufficient. So the current balloon that you will see and you can purchase are those that are 180° And apart and 10 sensors long. And with this device we were able to actually create a come to a pattern for refunds in someone that has normal esophagus. These are essentially the four sensors, the four strips anterior, lateral, posterior and the right and the 10 sensors. And what we found was essentially the pattern that emerged is high and my values that stays high for normal. Lower my values that stay low for Ohio and lo and my that normalize approximately. So again, this is the contour recognition. You see this, This is reflux E and normal. This is now the balloon that you can purchase again. 10 sensors. You see the sensors here, who strips separated by 180°.. These are the strips you can actually sue through the balloon, opposing the after feeling right here. Looking above. Using that balloon we wanted to reproduce and see if our original proof of concept data could be reproduced and indeed they were. Here's here's the oe low numbers that stay low. Here is good and here is non good and again contour pattern normal. And a patron with GERD that has low. Am I? The red colors versus normal oxygen. The other concept that's unique about me. Coastal integrity is the concept of cutoffs versus probability. This is um almost sacrilege speaking of this, but I'm going to because we really need to change the paradigm and the paradigm of cutoffs is somewhat not biological. What do I mean by that? Well, currently, what do we do? We do ph testing and decide what the abnormal cut off would be. Right. Some use 4.2%. So anyone above 4.2%, reflux on a 24 or 48 hours is abnormal, so I'm used 5.5%. Is the cut off. The Leon classification, says 6%. Some use the mister come on top of that at symptom index and symptom association probability. But guess what? They also have cut off S. I. Is cut off of 50%. S A p the 95% with impedance, ph cut off his 47 or 72 with Billy Tech with dress tag with Pepsi and I can go on and on. These are die economists cut offs. Right? So here the cut off above that, you're abnormal. Below that, your normal we're comfortable with that. That is a comfort zone. And I'm gonna push you beyond that comfort zone. And it's going to hopefully take you not long to say, well, this is novel. This is different. And it is This concept of cutoffs, by the way, is not biological, right? So, you do know that a disease is a spectrum. It's not all of a sudden at 6.1%, someone has the disease and at four they don't have the disease. So that's somewhat us created, which is really created a lot of clinical difficulties. So looking beyond that, can we use probability? What do I mean by that? All right. So remember, this is cut off again for reflux disease? Someone with esophagitis or non erosive. Look at the overlap despite this cut off. So it makes us feel better. Same thing with the billy Teck measurement using cut off but high level of overlap. So by the way, am I has cut off. So look at the over latin, America and esophagitis and abnormal ph from the norm. There is an overlap. So if you use a cut off, you're gonna have overlap and then you're going to call some people that have a disease normal versus not. What if we use probability? And that's what I wanted to talk to you about. So what mucosal integrity software does? It actually uses the concept that the concept of intercept and slope. What do I mean by that? Is that in a patient with the O values are low and stay low. There's low level of the slope is low and GERD the values distantly are low, but the slope is higher and non GERD the values are high and the slope is low. So can we use that probability and use it clinically. So here's a picture of the intercept and the slope. Someone with the OE has a low intercept. So low numbers distantly and the slope is low. So that's the O. E. And here's the probability measurements. Someone I'll go to normal. Someone that has a high intercept, I. E. The values distantly or high and they stay high, not much slope. They are non gert or healthy or normal. And then GERD is somewhere in between. We can then create probability based on various measurements and say that this patient has experts and probability that falls within non gert gert or yo why is that helpful? Well that's helpful because that's what we do. Clinically a patient that comes to you, a 30 year old that comes to you with this phase of food imp action. You've already created a probability of what the diagnosis might be. That's called differential diagnosis. We've been taught that during medical school that you create a differential that's based on a probability. We just don't have numbers. So we're putting numbers behind it based on raw data. And these numbers were hoping to tighten even more as we collect more and more data. Hopefully with our colleagues at different centers that are doing this device, we can then come up with a better measurement of what is the probability of the disease in this group of patients. So let me show you a video to put this in perspective. This is a patient that we scope. So what do we see? We see low numbers that essentially, I'm sorry, high numbers of M. I distinctly stay high. This is the contour. And guess what When we look I'm sorry when we look The software nicely creates this probability measurement in this case 74 likelihood that the patient is not reflux Norio. And then you say yeah, that makes sense because not only is this measurement telling me this patient doesn't have reflux, but I also know that the patient has chronic cough didn't get better on twice daily therapy. This makes sense. So you put all of those probabilities together and then you create a diagnosis down here. Normal patient, non reflux patient, whatever you want to call that. All right. So now let's go to this patient and here's the measurement. You notice very low stays low probability 76%. This patient has um you may not need any coastal integrity to tell you that if endoscopic Lee there were furrows and rings but it becomes an adjunct diagnostic test. Who your clinical suspicion you could argue. Well what I would have to biopsy anyway I would then ask you why and again this is gonna blow some people's mind. Well that's how the disease is diagnosed. Why. But that's what we do. Well those are the things that you have to question. So could it be used about uh E. O. And then tell us how well the patient as we cover I. E. What is the impact of therapy we have shown. In fact Doctor Cats feel from the Mayo Clinic has done studies using this device Andy ou patrons showing recovery of the epithelium post therapy. So could this be used in that fraction instead of keep biopsy? Ng it. Again. The opportunities are enormous. Here's a patient that comes to us and says I have heartburn, I have regurgitation. I take my patient. I'm sorry my P. P. I. I feel great. I don't want to take it. You're considering endoscopic or on the application. So now you do this test and what you see is low and mucosal integrity distantly, which then recovers approximately. And what you see here, the probability 65% this patient has reflux. Well you put that in line with your clinical suspicion and probability. Then what you do is you say this patient has reflux based on normal endoscopy but abnormal impedance. So I have only two more slides. This is I don't want you to read this algorithm for reflux. But look at the complexity and any time something is complex, it says there is uncertainty. Can we make it this? Can we make it so that if you suspect someone has reflux, whether it be a sarcophagi or extra Safi geo, you do empirically treat if symptoms improve. You tried great. If they don't want to take their medicine, you take them off. You do need coastal integrity and endoscopy and you're done and you send that patron if it's abnormal to surgery or endoscopic therapy, vice versa. If they did not get better and you tested them on or off therapy and if it's normal, you're done. You don't need to put a catheter in that patron. You don't need to do manama tree for placement of the catheter PHR impedance and you don't have to do bravo ph because you're done. So you don't have to wait 96 hours or 48 hours. I hope that that's where we will be. We do need to do a lot of outcome studies with this device. But we're all excited about where this is going. Uh and I hope that you found this talk helpful. And I look forward to the Q. And a section where we can have interaction. Thank you so much.
