Presenters: Mark Juckett MD, University of Wisconsin Hospitals and Clinics; Jonathan Moreira MD, Northwestern Medicine Hematopoietic Stem Cell Transplant Program
This is a video of a workshop presented at the 2019 National GVHD Patient Summit, Chicago IL
30 minute presentation, followed by 30 min Q&A
Summary: Graft-versus-host disease often affects the gastrointestinal system, and sometimes the liver. Prednisone is usually the first line of treatment. Other medications and therapies are available if prednisone, alone, is not effective.
- GVHD of the GI tract is very common after transplant, particularly if there is GVHD elsewhere in the body
- Symptoms of GVHD mimic those of other diseases which should be ruled out before a diagnosis of GVHD is made
- People with gut GVHD often have problems digesting food, which leads to other problems such as weight loss
- Consulting a nutritionist, exercise, managing depression and returning to a normal life-style can help with weight loss problems
03:19 GVHD of the GI tract usually starts as acute GVHD
05:10 Symptoms of GVHD in the esophagus include nausea, diarrhea and weight loss
06:20 Most frequent symptom of GVHD in stomach and colon is loss of appetite
10:34 People differ in which particular treatment is effective for them:
14:21 When people have GVHD in the gut, eating a very simple diet may help with symptoms
15:16 Some drugs used to treat GVHD can cause additional GI problems:
18:24 Symptoms of GVHD in the liver can look like viral hepatitis or gallbladder disease
20:12 Medications used after transplant can be hard on the liver
22:08 Weight loss is common after transplant, even among those who do not have GVHD
37:35 The role of microbiome in patients with GVHD
Transcript of Presentation:
00:00:00 [Moderator] Introduction of speakers: Good afternoon and welcome to the Graft-versus-Host Disease of the Gastrointestinal Tract and Liver workshop. This session is designed to be interactive, but please hold your questions till the end so that we can save time and we can get through the presentation.
Before we begin, Dr. Couriel was going to be presenting today but at the last minute was unable to attend, so we are very thankful that Dr. Juckett had agreed to step in at the last minute to help with this presentation. And now I would like to introduce our presenters, Dr. Juckett and Dr. Moreira, and let's give them a warm welcome as they go through their presentation.
Dr. Juckett is the Director of Hematology, BMT Clinical Research at the University of Wisconsin, Carbone Cancer Center, and the head of the graft-versus-host disease clinic.
Dr. Moreira is a Hematologist Oncologist with the focus on hematopoietic stem cell transplantation at Northwestern University's Feinberg School of Medicine. His research interests include the clinical trial development to optimize conditioning regimens for stem cell transplantation, and new preventative measures to treat graft-versus-host disease. So please join me in welcoming these two physicians. Thank you.
00:01:23 [Dr. Juckdett] Hi. Good afternoon. I know that I've got the post-lunch slot which is always a little dicey, so what I'm going to try to do is work through the slides relatively quickly so that we have plenty of time at the end to have a conversation, which is where I think a lot of the good learning occurs. I was very happy to see my high school senior picture is alive and well, so, we'll keep that there, and as she mentioned, I am covering for Dr. Couriel who at the last minute couldn't be here today. So, with that, we're going to talk about graft-versus-host disease in the GI tract, and this is a big issue, and I will point out that I'm... Dr. Couriel was kind enough to provide the slides that he was going to use, so that's what I'm going to follow here.
00:02:14 GVHD of the GI Tract is common, particularly if there is GVHD elsewhere in the body: So the first question is, how often does this occur? Is this a common problem, and I would imagine a lot of you are here because it has occurred, so you're well aware of the possibility. It turns out that involvement of the GI tract is pretty common, usually in the setting of having chronic GVH in other areas. And the reason from a doctor point of view, and that its important, is somebody that has chronic GVH in many different places, then thinking through the diagnosis isn't quite as difficult as it is in somebody who only has GVH affecting their GI system, because some of those symptoms like nausea or mild diarrhea or weight loss, where the list of possibilities to explain those is huge. It's enormous.
And so, obviously, we want to be very careful about making the right diagnosis and we really need to take all this information together to make sure that we're doing the right thing.
00:03:19 GVHD of the GI tract usually starts as acute GVHD: So, what's common? When GVH affects the GI tract, usually it will start as acute GVH, and acute GVH in the GI tract is usually much more obvious. It's the sudden onset of really, really bad diarrhea, or it's a sudden change in the ability to eat, whereas eating maybe was going okay, somebody's about a month out and they're getting better, then all of a sudden they just can't put a bite of food in their mouth.
That's a very distinct pattern. Also, early, in acute GVH, sometimes we will suddenly see the bilirubin, the liver test, go up in a particular pattern that reflects usually gallbladder disease but here it's different. It's acute GVH. So people that have acute GVH often, after the acute GVH subsides and things get better, go down the road three or four months and you may start seeing similar symptoms again. It's not acute anymore. Now it's chronic, so now it's something that's lingering. It's not going away so quickly.
So, we have the GI tract, as we know, is really what gets us through the day. We've heard the expression, "Ain't nobody happy if mom ain't happy," and I think nobody's happy if we're not happy between our nose and our behind. Our GI tract really has a lot to do with our quality of life and what our days are like. And so, the symptoms of graft-versus-host disease in the GI tract can be numerous affecting all these different parts from beginning to end, starting with the esophagus.
00:05:10 Symptoms of GVHD in the esophagus: The esophagus is a swallowing tube that is a very strong muscle, that has a very coordinated, a very sophisticated way of moving food down into our stomach, and little things can really make that not go very well. So any kind of inflammation in the lining of the swallowing tube, the esophagus, particularly inflammation that leads to scarring, now you've got a situation where people really can't swallow. So, there can be pain when people swallow, it can be difficult, it can make it hard to eat any kind of solid, and this is something that can come on very slowly over time, so sometimes people don't even notice that they're altering their whole meal plan simply because they're afraid of eating solid food.
So, the only way to figure this out really is for people to be put to sleep and for one of the GI doctors to take a look down in there and see what's going on, and fortunately there is a relatively straight-forward approach of, if there is a what we call a stricture or a narrowing, these can be dilated pretty easily.
00:06:20 Symptoms of GVHD in stomach and colon: Now, other symptoms, as we get down to the stomach and all the way down into the colon, when there is GVH, so GVH is a type of inflammation that can occur anywhere through the GI tract, as I mentioned, and there can be all kinds of different symptoms. The common symptoms are simply loss of appetite. They really just don't have any appetite. Where maybe things were okay for a while, now it's six months after transplant, I should be feeling better, I have no appetite, I can't eat. People have a tendency to lose weight. If the inflammation is worse it may cause nausea, vomiting in particular. When the inflammation from GVH affects the colon, the colon's job is to take the water out of what flows through our GI tract, so if the colon is not working, we have diarrhea. And so, any kind of diarrhea can be... Of course, there's many things it could be, but it certainly can be graft-versus-host disease.
And so, if you put these things together you can imagine what the person might look like who has this. They may lose weight, they may be very tired, they may have difficulty just looking at anything on a plate and just really not wanting to eat, and this is upsetting. It's bothersome. People can be depressed, and it can sometimes come on so slowly that, you know, we adjust every day, we make the best of a day, make the best of the day. A month goes by and suddenly people are in a bad place and they don't even realize it. So, it's something that can be very subtle.
00:08:02 GVHD of the GI tract is best treated with steroids: Now, graft-versus-host disease remains today best treated with steroids, and so, prednisone. I think almost everyone here I'm sure is very familiar with that, and unfortunately prednisone remains the one medicine that is most effective in getting control of this inflammation. Has plenty of side effects and other things that people are very familiar with, but this almost always is a place to start. Now there are some other things that can be done, and so, this is just a very short list of different medicines that are used. One of the prednisone-like medicines that we can use is these medicines can be formulated in a way that they're not absorbed very well into the body, but they apply that steroid effect just on the intestine itself, so a little bit like using a steroid cream on your skin, you can take a pill, budesonide or beclomethasone, and this is a way of simply applying the steroid just to the GI tract alone. And these medicines can be very effective and also minimize the effects of prednisone. So, these are great options.
00:09:14 Other medicines and therapies used to treat GI GVHD: Now, listed below is listed Infliximab, Etanercept. These are medicines that are approved. I think everyone probably sees the ENBREL commercial maybe five times a day, so, it can be used for all kinds of different inflammatory conditions, psoriasis and things like that, but it also has an anti-inflammatory effect in the gut. Infliximab is another medicine like that that affects some of the hormones that drive inflammation. ECP Photopheresis is an option, and then, currently, we've got some other medicines. Ibrutinib, IMBRUVICA, is now actually the only FDA approved drug to treat chronic GVH so that's out there.
Ruxolitinib or Jakafi is a medicine that's also out there to treat graft-versus-host disease, and that's something that can be effective. Sirolimus is another medicine that some of you may heard of, that can be effective as well. So, fortunately, our options are growing, and what we don't know is what's the best mixture. Is there a best way to start with this and then do that, and so what ultimately it becomes, is that everyone is sort of their own personal experiment.
00:10:34 People differ in what particular treatment is effective for them: We start with what we think may work best and we try to get people, then, off of that if it's not working very well. And we try something different. And it's very interesting to me, I've been doing this for a long time. People are remarkably different in what particular treatment works for them, so we really have to keep our eyes open and listen very carefully on what's working and what's not.
00:11:00 Photopheresis is a treatment for GVHD of the GI tract: For those of you maybe who are not familiar with photopheresis, this is a very interesting type of treatment that was created a long time ago primarily to treat a type of cancer, a type of lymphoma. And what they found is that the treatment also tended to affect how the immune system works. The way this works is, people get hooked up to a machine, blood comes out a IV tube into a bowl where it's spun. And when it spins it separates and you can remove the immune cells and then shine a light on them, and that light will inactivate those cells. And then there's something about giving those cells back helps influence how the immune system then subsequently works.
It's a very interesting thing, it's complex. There are a lot of studies, maybe more studies about using photopheresis than anything else we've done. We still don't really know how it works. So, it's out there. It can be effective, but it's really a very interesting thing from our point of view.
00:12:10 People with GI GVHD don’t digest food well, which creates additional problems: There are a lot of dietary concerns that people have, who have GVH. So, in addition to having problems with nausea, problems with diarrhea, the other common problem is that people simply don't digest food very well. And so, digestion of food is super complex. You think about all these organs in our body, our gallbladder and our pancreas and our liver, all these organs really work together to digest food. And if things really aren't working very well, then the food doesn't get digested, and undigested food is also something that can make people feel terrible. So, the germs in our guts can take undigested food and make a lot of gas. It can create just awful-smelling bowel movements, a lot of cramping, a lot of discomfort, which may have nothing to do with GVH other than the fact that it's food that's not being digested well.
And so, this is one of the things we have to think about when people are still having symptoms. Is this GVH directly, or maybe this is something about how their digestion is working. So, sometimes, for example, we can actually give what are called pancreatic enzyme replacements. These are the enzymes that help digest the food in a pill, and people can simply take these with food to help the food digest. Lactase is also a pill that people can take to help digest lactose, which is the sugar in dairy products, that also can cause a lot of gas and stomach upset. And there's also a medicine, I think it's on this... There's a medicine called cholestyramine, that can help bind bile acids that can also contribute to diarrhea.
I am bringing this up to you, this part of it can get very complex, and again, often you don't really know what's going to work until you just give it a try. Let's try this for a month and see if this helps. If it doesn't help, you stop it, maybe try something else. There is some aspect of trial and error.
00:14:21 When people have GVHD in the gut, eating a very simple diet may help with symptoms: The other thing that this slide's alluding to is the fact that foods are different in how hard it is to digest. So, any of us that have kids have heard about the brat diet. You know, if a kid has some kind of GI illness you give them this real simple things, bananas and apple sauce and toast, food that's very easy-to-digest food. Some of the digestion of this food actually occurs in our mouth before it even hits our stomach.
When people have GVH sometimes it can be really helpful to eat a very simple diet. You know, that big hunk of prime rib, that takes all of muscle that you can put together to digest. On the other hand, simple noodles and rice and things like that are very easy, so that can really make a big difference, and this is where a dietitian can sometimes really be great friends of our patients in finding things that can help.
00:15:16 Some drugs used to treat GVHD can cause additional GI problems: So these are just some other drugs that are used to treat GVH, where actually they can cause some problems. And so, one of the classics is a medicine that has this long name, we'll just call it MMF. So this is a medicine that's used a great deal on the solid organ folks. We don't use it quite as much for GVH at this point, but it's still out there and something that's used. It, by itself, can cause diarrhea by creating a certain inflammation just through the absorption of the medicine. So we have to keep our eyes open about medicines that we may be giving that could actually be causing some of the problems.
Tacrolimus and cyclosporin can directly cause diarrhea. And anybody that's been on tacrolimus might remember also having to take magnesium. And so, what's magnesium but the first M in Milk of Magnesia, which is what we all use for constipation. So magnesium is a very strong laxative. So we really have to be very careful, again, about how we're prescribing these medicines that could potentially make things worse.
00:16:29 Diagnosing GVHD of the GI tract requires excluding other conditions with similar symptoms: I mentioned a little bit earlier that when people have GI symptoms, there's a very long list of things we have to think about. So, in contrast to somebody who shows up with a bright red rash at a certain period after transplant, 99 out of 100 times you can just look at somebody and know exactly what that is.
This is very different because somebody that has bad diarrhea six months afterwards, there's a lot of things that could be happening. So, from a doctor point of view, I really have to put my thinking cap on. I got to think about all these other possibilities and make sure I'm not missing something. And it is so important because if you look at the list, while we have GVH on the list, and that's something for which we would give medicines to slow down the immune system, most other things on here, all of everything on here, is an infection. So, the last thing we want to do is slow the immune system down in somebody that has an infection that's not treated. So we have to be very careful about this.
The last mention that he's got here is, obviously, if there's a concern about somebody's disease, original disease, occasionally there can be symptoms related as well.
Now, this is a very rare condition that he's alluding to. There's a condition called cord colitis which is an interesting thing. People that have had umbilical cord transplants can develop a very unique type of diarrhea called cord colitis, which seems to possibly be due to a very unusual type of bacterial infection that may come with the cord. And so, this is a relatively rare event. Nothing that is very likely to occur, and when it does, it occurs very early after the transplantation.
00:18:24 Symptoms of GVHD in the liver can look like viral hepatitis or gallbladder disease: Now, the other organ that is part of our GI tract is the liver. Liver, super important. Detoxifies our blood, helps manage all of the medicines that we use, helps get rid of those. And GVH can affect the liver in two ways. One way is to affect the tubes that carry bile to the GI tract, and the other way is to affect the cells themselves.
So, on one hand we have a pattern that looks like somebody that might have gallbladder disease, the other pattern looks like hepatitis, looks like viral hepatitis. And so, either presentation can occur and when it does occur, once again, we have to be very careful by making sure that we have the diagnosis correct. Because if somebody is six months later and we see some of these tests go up, well, it might be gallbladder disease. It might be they have a stone.
If there's evidence of hepatitis, it might be GVH or it might be hepatitis. We recently had an outbreak of hepatitis E in Wisconsin, and that's something that's in the community. People get it by eating food that's not cleaned very well, and obviously that's a situation where the worst thing that we could do is treat that person for GVH when in fact they have hepatitis. When we do see the changes in the liver, almost always we're going to want to ask for a biopsy to really try to nail this down to make sure we know what's happening.
00:20:12 Medications used after transplant can be hard on the liver: Again, in the liver, we always have to think about medicines. Liver is responsible, really, for metabolizing all the medicines that we give people, and many of these are hard on the liver. And so, especially medicines that are very important, like fluconazole and voriconazole, these medicines can be pretty hard on the liver, and we know that many of you are on many medicines that not only can be hard themselves, but they interact with each other and so there's really a lot of thought that has to go behind sorting that out.
00:20:47 Initial treatment for GVHD of the liver is usually prednisone: So, how do we manage GVH of the liver? The first part, again, our initial go-to medicine is always going to be a medicine like prednisone. It doesn't always have to be prednisone. Sometimes it can be very mild, and there is a medicine called Ursodiol. That's Latin, I think, for bear gallbladder. I think is where it was originally came from, so gallbladder from bears. Ursodiol itself is really nothing more than a soap that you can take and it goes through the liver to sort of clean the liver out, and it has an anti-inflammatory effect. And so people that have mild chronic GVH of the liver sometimes will get better just by clearing out the tubes with the Ursodiol. That can be very effective by itself, and there's some actually options like Ursodiol that are available as well.
And then, once again, if these first medicines don't work, photopheresis is something that sometimes we can use. And then all the other medicines that I mentioned before can also apply to treating GVH of the liver.
00:22:08 Weight loss is common after transplant, even among those who do not have GVHD: A lot of people get concerned about weight loss, so let me just talk about this for a minute. Weight loss is very common after transplant. And so, a handful of years ago, we pulled together about 500 people that had been through transplant and found that over the first three to six months people lost, on average, about 10 to 15% of their body weight. That was average. After that period of time, there tended to be a weight gain, and so, in fact, there tended to be too much weight gain.
This is what occurs as part of the natural process of going through all of this. And once again, weight loss, by itself, might mean GVH but also might be somebody that's just gone through a very difficult course, hasn't been eating very well, so lost weight and gradually regains it. So, when we see weight loss, we think about GVH but we have to think about all the other things that people go through, once again, and really not just be narrow-minded and think about GVH alone.
In terms of why people lose weight, I think I mentioned the caloric intake. The other part of weight loss is sometimes the appetite gets so restricted, people just don't have an appetite for anything that has any calories in it. And so, somebody that's just eating some white rice a few times a day, that's about this many calories. If that's the only thing that works, this could be very difficult.
00:23:43 Dietitians can be helpful in managing weight loss: So, in that setting, again, our dietitians can be really helpful. Different kinds of protein supplements can be really helpful. They have these now, they're plant based, they can be soy based, they can be milk based, whey based, so there are different ways of getting different kinds of protein supplements that carry different kinds of substances that people can consume without too much difficulty.
The last thing that's mentioned here is just depression. So, we know that people that go through a transplant, it's a very long ordeal. People can stay up just for so long before hitting the wall. And so I think we all acknowledge that just depression of itself can sometimes really make quality of life poor.
So, managing weight loss, I identified some of this. Getting a dietitian early is very important.
00:24:21 Recovering a normal pattern of life can help with weight issues: There's really a need, I think, to be much more engaged in helping people recover a normal pattern of life. And so a normal pattern of life for us includes going out and working and pushing ourselves and then we rest and then we sleep well at night and we do it again the next day. And when people don't feel well and their life is disrupted by being in the hospital, going to the doctor all the time, it's very difficult to have that pattern.
And so, identifying that need, setting a pattern, setting a schedule where people are working, which could be nothing more than walking to the end of the block and back, and then resting and making sure they're sleeping at night, engaging in family, attaching themselves to some purpose they had in the past, these are all the components of getting better, and all are part of getting people through this, and it definitely ties into the diet.
00:25:41 Strategies for weight gain: So, strategies for weight gain. There are some medicines that sometimes can help. I identified some of these protein supplements can help, and that's where the dietitians can help. Simple things like just olive oil. Olive oil is very healthy, has a ton of calories, you can put olive oil on lots of food and that's one way of getting the calories up.
The exercise makes a different, and again, it doesn't have to be running 10 miles, it can be a walk to the end of the block, but the heart rate coming up stimulates appetite. And if all else fails, sometimes we actually have talked to people about getting [feeding] tubes and getting them over the hump, because people can get malnourished to the point that it's almost like they've gotten so weak they just can't get up again. And we have to get them beyond that wall.
00:26:29 Managing GVHD in the GI tract is challenging: This is just a way that we help keep track. So at our particular clinic I have a very well educated nurse who does all the evaluations on a particular schedule, so we can keep very close tabs on all the symptoms and things that are coming up. So we do this in our visits. And I point out that there are a lot of occurrences, meaning events, that can occur that will reflect GVH. The big one we mentioned earlier was developing an area of scarring in the esophagus. That's a clear sign of GVH. Identifying somebody who's not absorbing food, in and of itself, is a sign of GVH. And so we really have to think very broadly about all of these different parts that could be happening.
All right. And I think this is a way of saying that, managing GI GVH is very complicated, and so, there are physicians that focus on this, the nurses that focus on this, the dietitians that help with this, and it usually takes a larger team really to get people through these events. So I think that's my last slide. Some conclusions here, and we'd like to open it up and hopefully have some conversation. Thank you.
Questions and Answers
00:28:01 [Audience] Should patients get a biopsy for GVHD when going for a colonoscopy: My husband had the transplant, and he had graft-versus-host disease and he continues to have some skin, some... a lot of... When he goes to get a colonoscopy, should he get a biopsy for a graft-versus-host every time, or... just if he's having diarrhea, or what?
[Juckett] I think in general, when somebody is going through a colonoscopy, we have to think about what's the purpose. And so, if the purpose is something very simple like screening for polyps and people feel fine, in that setting usually you wouldn't do a biopsy because the biopsies carry a very small risk, and there's nothing that specifically we're looking for that we would want to do something about.
If people are going through a colonoscopy because they're sick, that's different. Now, you really need to cast a pretty wide net, as I mentioned. This could be a very tricky thing. And so, in that setting, you can only tell so much by just looking with your eyes. So, the gastroenterologists are very good, a little bit like the dermatologists, they can just see things and know that there's something wrong. But their eyes are only so good. And particularly if there's evidence of inflammation in the colon or anything that doesn't seem right, that should be biopsied.
So I don't know if that answered your question. I think the point is that you want to do biopsies when you think it's going to matter, when you're trying to figure something out, because there is some risk and you don't want to put people at risk that's not necessary.
00:29:45 [audience] Is it common to want food at a restaurant but only be able to eat a little: Thanks for your presentation. I've got just two questions. I'm 18 months out following a stem cell transplant, and I have a bit of GVH, mostly skin related., But I have had episodes of diarrhea and I did have C. difficile diarrhea in the hospital. I've been on multiple antibiotics for a long period of time, and it's what you get.
So, my question is, I lost a tremendous amount of weight during the process. When I went into the hospital I weighed about 265 pounds. I came out at 183. I'm up to about 225 now, and my weight is sort of fluctuating, but the question is, somebody who's going through that process, I will look at a menu at a restaurant and say, "Oh, I want that," but when the food comes, I can maybe only eat half of it or quarter of it, so, like, my eyes are bigger than my stomach or my appetite can consume. Is that a typical reaction?
[Juckett] I think it is. I think it is. We have kind of a mental wiring that keeps our bodies in a certain area, and that's, day by day, that's how we live. When you go through something like a transplant, that mental wiring is still there, but there is disagreement with what's going on down below. So, I would say, what you're describing is far more common than agreement. And what I would suggest is, we tend to grow up in families where your parents were telling you to eat everything...
[audience] Yeah. Clean your plate. Yeah.
[Juckett]... if you don't eat everything, you feel bad about it. And that we just let that go. And buy things, make things that you're interested in, take five bites and give yourself a break and don't worry about having to eat everything. Because even eating a small amount of food helps things heal. And so, getting a small amount of food is better than trying to shove the whole thing down and feeling awful for the next six hours.
00:31:54 [audience] When is it safe to eat fresh fruit and vegetables after transplant? Good. And my second question is, since the transplant, so it's been 18 months, almost two years, I have avoided fresh vegetables and fresh fruits because of the concern of bacteria in the lettuce and the romaine lettuce and my wife is hyper vigilant about it. So I haven't had a salad in a long, long time. And I haven't had fresh fruit... She'll give me a banana, that's about it. So, what was your thought about the relationship between, when your immune system should be sufficient to be able to accommodate commonly found fruits and vegetables, versus...T
[Juckett] This is a huge question. So I'm-
[audience] That’s why I'm asking. Because I'd like a salad every once in a while.
[Juckett ]I'm going to acknowledge that I'm going to give you my response, you can probably put 10 doctors in the room and get 10 different responses because there's no agreement about this. So I'm going to tell you what we do.
So, there's pretty good evidence that once the neutropenic period is over and people are out of the hospital, that there is no reason for any real dietary modification based on the risk of infection beyond what we'll call safe food handling. So, produce should be washed, meat should be cooked, eggs should be cooked. Don't go eat sushi in the middle of Wisconsin at the corner bar. Go to places that know how to handle food and beyond that, eat the healthiest diet you can stand, because a healthy diet has so many beneficial effects for people in general, that we want people to eat a healthy diet and that includes fruits and vegetables.
[audience] Okay. Great. Thank you very much. Wish my wife could be here to hear that.
[Moreira] What Dr. Juckett mentioned. To answer your first question, one of the strategies that I employ with my patients is encouraging them to eat several meals that are very small throughout the day. So, as opposed to the typical three large meals a day, or two big meals a day, because sometimes people might skip breakfast or lunch or what have you. Try to do four, five or six meals that are very, very small in size. It makes it easier, it still helps get the number of calories that you need in, and it also makes it a little bit more tolerable on your gut.
To answer your second question, I agree. I think we're already dealing with, or our patients are dealing with the challenge of having a restricted palate secondary to the conditioning regimen that they've had. Secondary to depression that can come along with it, and secondary to the issues that you're illustrating in your first question. So, to further restrict it becomes a bit more of a challenge. It's always a conversation that you have to have with your doctor. Maybe if you've had a particular issue with recurrent infections or something, there might be a little bit of cause for concern and what kinds of fresh fruits and vegetables or raw foods that you might be consuming.
But overall, I try to employ the see-food diet mentality. So if you see food, you eat it, within reason, of course. With the same restrictions that he was illustrating.
00:35:12 [audience] Question about inability to gain weight and gas from undigested food: I'm one year further than the last gentleman, and at 18 months I had a whole GI system reset because it messed up and was bad. But now I have had 3,000 calories a day, I'm 144 pounds. I can't put on weight, and it cycles, but sometimes I have 10 times the gas I normally have, and you were talking about gases from food not being digested well. I don't know if it's my gut biome that changes or something, but I can eat the same foods and have totally different reactions, and am trying to understand that a little better. So, okay, and nothing makes a balance for me and this stuff. Do you have any suggestions on this?
00:36:04 [Juckett] Maybe we should both weigh in on this because I think this is another thing there's a lot of variability in approaches. What you're asking actually is a very complex question because our metabolism is a very complex process that changes over time. We know that people, as they get farther beyond transplant, they tend to have... metabolism looks like something called metabolic syndrome which is where people hyper consume calories. They have the tendency to have high blood pressure and they have a tendency to have diabetes, and so in that setting, sometimes altering the nature of the diet makes a difference. And so particularly avoiding things like sugar, too much carbs, favoring protein and fat, that could be part of it.
00:36:53 [Moreira] Definitely there are medicines that make a difference. So when people are on prednisone, for example, and if particularly, initially, a lot of the weight loss is due to muscles shrinking.
And so, prednisone definitely inhibits building up muscle, and that could be part of it. And, unfortunately, age still plays a role. So, as we get older, your body just doesn't build muscle the way it did when you were 18, and so the idea of building muscle back occurs much more slowly as people get older. So, medicines, metabolic changes, and actually the nature of the diet itself, those are some of the factors that can affect that.
00:37:35 Role of microbiome in patients with GVHD: To add onto those great points. You alluded to the microbiome, and for those of you who aren't familiar, although I imagine this audience is fairly savvy, the microbiome refers to the population of bacteria that you have in your intestines. And by some estimates there are about 10 times the number of bacterial cells inside your gut than cells make you up as a person. So there's a huge body of emerging data, not just in graft-versus-host disease and in hematopoietic cell transplantation, but throughout the spectrum of medicine recognizing the increased role that the microbiome plays in immune regulation and the development of cancers and a whole range of chronic illnesses, hypertension, what have you.
So, the microbiome is also pivotal in the breakdown of certain nutrients and the absorption of certain nutrients, right? Our gut is a fantastic organ that helps break down that porterhouse or that prime rib or that corn on the cob that you're eating, and convert it into the necessary nutrients that we need to grow and to thrive. But the bacteria in our gut, and to some extent, even the fungi in our gut and the viruses in our gut are pivotal in breaking down some of those compounds into foodstuffs, into nutrients that our gut can more easily absorb. So, with the antibiotics that you've been exposed to, with the immunosuppression that you've had, with the reset that that immune system has had in your body, that also alters the communication between the microbiome and its composition to you and your body. So, yes, I think that can play a certain role in the efficient absorption of some nutrients.
00:39:18 [audience] Are probiotics helpful for patients with GVHD: But that doesn't mean I should play around with... oh, get these probiotics and stuff. They-
[Moreira] So, that's a very good question. I think we recognize that although trying to establish a healthy, diverse gut microbiome is helpful, there is a big caveat to that. Depending on where somebody is and along the lines of their transplantation, bacteria don't have brains. They don't make a distinction between when they're causing you ill and when they're benefiting you. They don't have like an on switch and an off switch as to be good or evil. So, I think that's a discussion that you should really have with your physician based on what kind of outcome you've had, how well you've done with regards to your transplant. If they feel that there might be a potential role in trying to be a more overt in modifying the gut microbiome, truthfully, by trying to maintain a balanced and healthy diet, you should be getting some degree of bacteria in your gut that helps repopulate and reestablish some sense of normalcy in the gut.
[Juckett] I'll just reiterate that there are some studies that are fascinating about this microbiome thing. It's really unclear that what supplements do at this point, but the diet has a huge impact, and so I think this idea about truly eating the healthiest diet you can stand is without a doubt I think the best advice that we can give you. I think leave the supplements aside, pick up the broccoli and go with that.
00:40:56 [audience] Is the pancreas affected by GVHD: As a spouse, I can always tell my husband's graft-versus-host disease is kicking up when his stomach gurgles during the night, and we've learned the hard way. I always carry a extra set of clothes with you, with plenty of wipes and plastic bags, and scope out where the bathrooms are after going out to eat for a lunchtime. That certainly takes the stress out of going out. And why doesn't - the pancreas is not affected by graft-versus-host disease?
00:41:39 [Juckett] The pancreas can definitely be affected. It's not really clear how, we don't know how to predict it. It's not pancreatitis per se, but there can be poor pancreatic function. And that's what tends to lead to at least one of the reasons why people may have difficulty digesting food. And so, I think the story that you tell about your husband, I think important. I'll make a couple of points about it.
It could be that that gurgling, and what's going on, is because of actual inflammation itself. It could be because of, maybe, he's now not absorbing the food correctly. Something along those lines. But the fact that you notice that relationship I think is an important observation and something to let the physician know, because it does give us a little bit of an indication about where the problem is. People that have strictly colon inflammation don't tend to have the gas problem. They have the watery diarrhea problem. The gas problem tends to come when the inflammation's in the middle of the gut.
The other comment I want to make is that we had a grant a while back where we surveyed a lot of caregivers and one of the most frustrating things that caregivers had is, they would get to know all these signs and symptoms that their loved one would have. They would indicate things headed the wrong direction and their frustration was that nobody would listen. And so, I think there is expertise in the caregivers that's developed over time that we obviously really want to listen to because it's nice to pick up anything early before it's an overwhelming problem, and I just want to applaud you for having your eyes open.
[audience] I could smell something was wrong with my husband when he first was diagnosed, and when he relapsed the second time he had gone to the doctor about maybe five months earlier and said, his smell's changed, and sure enough, in time, he did relapse.
00:43:59 [audience] Question about liver biopsy: Thank your for the presentation. I have to get a biopsy for my liver in probably the next 30 days. Any... been up and down, my levels have been up and down for my liver. Any common things, after a biopsy, that kind of-
[Juckett] So, a couple of comments about that. The liver biopsy, itself, is something that nowadays is usually done by somebody who does a ton of these things and gets really good at it, and that's the person that you want doing the biopsy. So that's something you should feel free to ask about. What they want to do is make sure that your blood counts are okay, particularly the platelet count and that your blood clotting is okay, and if those two things are okay, then the odds of anything bad happening, having a complication, are very low.
I think getting the biopsy is really helpful because there are so many things that you can see on a liver biopsy that can have a huge influence on what the treatment may be, including, I mentioned this hepatitis E. I mean that's something that most of us we just don't see that, and yet, recently, there is an outbreak of hepatitis E and they think it might have been one of the... a tavern somewhere that somebody had some contaminated water. But I put that out there only to say that there's a lot of possibilities and it's important that they try to be very specific about exactly what's happening, because the treatments, these are not easy treatments. These are treatments that are hard on people, they carry some risk, and you really want to be pretty sure that you've got the right things identified.
00:45:55 [audience] Treatment for GVHD gut that causes stomach pain: The GVHD that I have in the gut, it's mostly the stomach pain, that's my problem because I usually don't go to the bathroom unless I have a stomach pain, so is there anything that can make that go down, because I'm taking Ruxolitinib now.
[Juckett] Oh, you are. Good. Okay. So, I think stomach pain is one of the more common problems that people have who have GVH in the guts, and part of the... particularly for younger people, the way our guts work is when you get a little bit of food in your stomach it signals down to the colon to empty out, to make space, and so a lot of young folks when they eat they have to go to the bathroom like right away. That by itself is pretty common, but it shouldn't hurt.
There are some medicines that you can talk to your doctor about that can tend to help with that pain, and these are medicines... So, let me back up. A lot of the pain tends to come when those intestines are squeezing. They're muscles and they're squeezing and that hurts. And so, there are some medicines they might be able to give that helps relax that squeeze so it's not squeezing so hard, and that's what I might suggest.
So, depending on the situation, what kinds of medicines do we use, in this situation? We would start with simple things that maybe he's had already like Immodium or Lomotil. Sometimes we'll use cholestyramine if we think that there's a bile acid problem, and those would be the ones, I would say, are what you might start with.
00:47:56 [Moreira]: Just to add on to that, sometimes with cramping, they can come along. We oftentimes we use a medication called Bentyl, which I think it's a dicyclomine, I think it's a generic thing, and so that can prevent some of that cramping that can be associated with bowel movements or with...
There's a lot of physiologic gut movement that's called peristalsis, and our gut usually does that. As a matter of fact, it's doing it probably as we speak. You might not even notice it, which is just part of what it might have to do, but these symptoms can become a bit more prominent when the gut's been irritated and altered, whether it's because of infection or GVHD, or a confluence of all those things. So Bentyl's sometimes a good adjunct that I've used for some of my patients who have these chronic abdominal issues, abdominal discomfort, and for whom we've worked out, made sure that there isn't any active GVHD, especially in the upper GI tract.
Either of the medications that you mentioned, Lomotil, Immodium, are also great adjuncts to helping minimize the frequency with which you're moving your bowels.
00:49:18 [audience] Lengthy question about son who has had GVHD, reactions to drugs, and other complications after transplant: Hello everyone. The doctors gave him octreotide, I suppose, to slow down the cramping. It helped, it helped a little bit, but then they can do that IV while you are in the hospital, and then when they discharge you they want you to go home with the injection. That thing hurts like crazy. So, my son got that one time and he screamed. I never heard him scream like that, so they stopped the octreotide. And then, during your presentation you said something about IMBRUVICA. They started him on IMBRUVICA.
He got that like for a month, and things seemed to be getting better because the stool output was getting less, but then he started to develop some kind of tearing, his eyes were tearing, and then it blocked the one side of his nostril, and we went to the hospital. They thought he was, what's that? Allergies. So they gave him something for allergies, but then five days after that, he still had the same problem. And then he developed into a very bad headache, like he was feeling the headache up here and he was screaming. So now they did the CAT scan and what's the other one? Imaging thing? MRI. And then they said, they discovered that he had a fungal infection.
So now, it was almost going to his brain. They had a craniotomy right away for him, but after that they said... Oh, there was this study that came up that people that were given IMBRUVICA developed fungal infection, as against those that didn't get IMBRUVICA, you know, they did not get that infection. So I'm trying to figure out, how come they don't get these studies before they start to give this medicines to the patients, and most of the times, this GVHD the thing we all hear have different diagnoses that resulted in the GVHD, but we all have something in common. Everybody has different kinds of pains and different symptoms.
So now my son has diarrhea which has been going on for a year, over a year now, and still they haven't been able to find something to help to make it better. He's been having this pain for over a year, has missed out ninth grade, but he did home instructions. We thought by now things would be better. But then I'm still asking the question, this GVHD, they do not tell you exactly what to expect when you go through this transplant. They just tell you, "Oh, GVHD might be a symptom, but, oh, we can take care of that if that happens." How come they haven't been able to find something to actually deal with this thing, from the source, especially that I found some rashes on his skin. I'm going to show you the pictures afterwards. And I complained that that wasn't a rash. This was something different, but nothing was done until a couple of weeks later when they got the report back that he was GVHD, after he was already having the diarrhea for two weeks, they started treating for GVHD.
I just feel that if something was done right away when we saw those rash on his skin, it probably wouldn't have resulted into his gut right away. So-
00:53:27 [Juckett]: Better tools are needed to diagnose and treat GVHD: I think that the... what is so difficult is GVH can occur in many different ways with a tremendous range of severity, and there's no question that we've got a long way to go to sort out how best to treat severe GVH. We don't have enough knowledge right now to know exactly the best way to pinpoint the best treatment for an individual, and so, what we're left with right now is a toolbox of tools and we pick the tool that we think is the best for the given situation and hope that that works. But we don't have a way of knowing what the best tool is until we try. I mean, unfortunately, I think that's reflecting the state of where we are.
00:54:18: [Moreira] Suppressing the immune system to control GVHD can lead to other problems: I'm very sorry to hear everything that you've been through and that you folks have been through this. This sounds like it's been an extraordinarily difficult ordeal.
When, just to add onto to what Dr. Juckett was saying, whenever we're dealing with trying to control GVHD, the underlying premise here is to suppress the immune response. Right? There's an over-activity of the immune system that the donor's immune system that is targeting the normal tissues. This is a by-product of what we're trying to do with the transplant, which is having that donor immune system attack the... to keep the leukemia or lymphoma or whatever underlying cancer that we've transplanted for in check. So when we're trying to control this immune response, the collateral damage, so to speak, or the side effect, is that we are also impeding the ability to adequately fight off infections.
So I can't specifically comment on what were the factors that directly led to the fungal infection in the brain. But we run that risk with any kind of treatment that we put patients on, and that's something that I, as a stem cell transplant physician, try to be extremely mindful when I'm putting a patient on prednisone or when I have a patient in the hospital and we have to think about giving them a second-line agent, or they've had a multitude of second-line agents to manage steroid refractory aGVHD. Infection is one of the most significant risks that patients can develop, and the longer that they're undergoing these immunosuppressive regimens, especially in severe GVHD, the higher that risk for infection is.
So, this is one of the great challenges and that's why we, especially at academic medical centers like our own, you know, University of Wisconsin and of Northwestern, we try to open and bring up clinical trials that might have new and novel therapies that hopefully can fine-tune the response to really target the cells that are leading to the GVHD whilst minimizing the impact that it can have on other aspects of the immune system. But it is quite clear that we have a long way to go and we try to approach this with humility because we understand that there are situations like your son who... We certainly want to do better because everyone deserves a high quality of life. This is why we do these transplantations, to give folks an opportunity to live longer and to live better quality lives.
I hope that can answer some of the concerns that you had.
00:56:52 [audience] Question about ways to stimulate the appetite: So, he has been on TPN [total parenteral nutrition] for a while, and he's kind of worried that he's not getting the weight that he want, because he actually lost weight, up to 26 kilograms, as at June of this year, so his weight came down to... He just started losing weight just, I mean, we couldn't explain. He just started coming down because he was on prednisone for a while, and that was helping him to eat a lot, so he was eating, and then they started to taper down on the prednisone and his appetite dropped. And he was struggling to eat still but just not getting enough calories, so he started dropping that weight, and to put him back on TPN, which is still on, as we speak, and they're not getting the weight that he still want, because he's still growing.
He say he doesn't have the appetite. I saw Marinol here. He got Marinol for a while. He said it wasn't helping, so they stop. So I was asking them, "Is there something else they can give him to at least stimulate the appetite a little bit?" So they said, "Periactin." He's been on Periactin now for months, and now he says it's not helping either, so I don't know if there's anything you can recommend that can at least stimulate his appetite to help him eat?And something else I just wanted to throw out there. We were able to find out this supplement for those who are lactose intolerant. There's this... or the supplement that we were able to find for him, that at least he could take for a little while. Now he's tired of it. It's like, any other thing that you just... after a while, you get tired, but it was helping him, at least, to take down some calories. The little box is about 300 calories and it's Kate Farm. It's plant-base. I have the picture here for those who have problems with keeping down the calories, and hopefully it's going to help somebody else. I'm just putting it out.
00:58:57 [Moreira] Thank you for that. From an appetite stimulant perspective, I think this is one of the vexing questions that always comes up in my clinic, and I'm curious to hear if Dr. Juckett has any more experience in that, but I haven't found a medication that I feel is universally effective. And I think it's because appetite is governed by so many different factors, whether they're physiologic, whether they're emotional, or a combination of all those things. So, I think, the Marinol is perfectly reasonable. I think you mentioned a couple of other medications on the list too, but I just haven't found a magic bullet, so to speak.
00:59:34 [Juckett] I would agree with that. Appetite is such a complex thing and the important driver of appetite is a healthy gut, and so it's very difficult for people to have a healthy appetite when there is inflammation in the gut, when GVH may be active, and I think none of the appetite supplements are really going to have a huge impact in that setting. The medicines that are out there, at best, have a very mild effect and one of the things that we use for adults, for example, is a medicine called mirtazapine, which is an antidepressant. I'm not sure if it's something that's okay for children.
One of the side effects of mirtazapine when healthy people take it is they eat a lot and get hungry and gain weight, and so we've taken advantage of that side effect. But at best the effect is mild.
01:00:28 [moderator] I'm sorry to interrupt you guys, these are excellent questions, but in order to get onto your next session, and if you want, I'm sure Dr. Juckett and Dr. Moreira will sit here for a few more minutes and answer a couple of personal questions that you have. Thank you, and have a wonderful afternoon.
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