Acute Versus Chronic GVHD

Jaime Shahan

We used to talk about graft-versus-host disease (GVHD) being a time-specific entity, where acute GVHD happened in the first 100 days after transplant and chronic GVHD was defined as occurring after the first 100 days. However, beginning with the 2005 NIH consensus document¹ and continuing with the 2014 update we follow today,² we have started to clarify that GVHD is a clinical diagnosis. Rather than just looking at timeframe, now we talk about diagnostic features because sometimes acute GVHD can happen after the first 100 days post-transplant. Some common times for that to happen are when we are withdrawing our immune suppression, or potentially when we give a donor lymphocyte infusion in the case of relapsed disease or dropping chimerism. (Chimerism is a test that looks at the DNA of the host and of the recipient; ideally we hope for 100% donor chimerism.³)

Diya, what are some of the clinical features that are specific to acute GVHD versus chronic GVHD?

Diya Sabnani

The clinical features of chronic GVHD are pretty variable but usually resemble autoimmune and other immunologic disorders. For example, scleroderma or Sjogren's syndrome, primary biliary cirrhosis, wasting syndrome, and bronchiolitis obliterans syndrome. Presentation can vary from these immunologic autoimmune disorders, but this is our starting point when we're talking chronic GVHD.

Acute GVHD affects the skin, liver, and GI tract. Starting with the skin, in acute GVHD, skin rash is common, manifested as maculopapular rash, with erythema. But in chronic GVHD, we sometimes see scarring and sclerodermatous changes. In the GI system, patients with chronic GVHD can experience webbing of the esophagus, and it becomes constricted. They feel like when they swallow, they can't get their food all the way down. That's how they describe it. With acute GVHD, the GI symptoms are usually persistent nausea and vomiting and diarrhea. But these symptoms can overlap into chronic GVHD and aren’t necessarily specific to acute or chronic.

Jaime Shahan

Yes, nausea, vomiting, and diarrhea can also sometimes happen in chronic, but you don't have that esophageal webbing in acute GVHD; that's more of a chronic feature.

Chronic GVHD can also manifest orally. Patients may have persistent dry mouth or mouth sores or ulcers that are red and painful, but one of the features that's more diagnostic for chronic GVHD is the lichenoid changes. I tell patients it's a little bit like a spider web on top of their mucosa. It looks like a little bit of a white patch or plaque, and it can be sensitive.

Some of the features that are distinctive but not diagnostic for chronic GVHD are mucoceles. They're like little blisters on the oral mucosa. Sometimes patients will say, "I can't eat acidic foods. I can't eat spicy foods. Every time I do, it burns and then there's a blister in my mouth, and it goes away after a couple of hours." That's a mucocele.

And even though acute GVHD doesn't manifest orally, sometimes these patients do have mouth sores. But it's usually secondary to chemotherapy and all their other medications—treatment-related.

Diya Sabnani

Also, if a female patient has oral GVHD, she could potentially have vaginal GVHD. Talking with patients about that is so important.

Jaime Shahan

Yes, it’s so important because that vaginal mucosa is the same type of mucosa as in the mouth. So when a patient has oral GVHD, we've found that being proactive in talking to patients about vaginal involvement and treating it is very important because the potential scarring can be irreversible, unfortunately.

Diya Sabnani

Some of those symptoms are going to be vaginal dryness, and, like we talk about with the esophageal webbing and constriction, it's the same thing with the vaginal orifice. With scarring, it can become difficult for a vaginal exam to be performed or even for coitus to occur. These are the key things that we should be talking about with our patients.

Jaime Shahan

Absolutely. Some of our women patients with vaginal GVHD will say that it burns whenever they urinate or that they have vulvar pain. Sometimes we also see redness or those lichenoid changes, called lichen planus. And then sometimes patients even have ulceration or fissures within that vaginal mucosa, which can be very painful and difficult.

Diya Sabnani

Shifting gears to other organ systems, when there is liver involvement, with acute GVHD we solely are looking at total bilirubin. But in chronic GVHD, we'll see a rise in ALT, AST, alkaline phosphatase, and potentially the total bilirubin. So we're taking into account the entire liver function panel with chronic GVHD.

Chronic GVHD can also affect the joints and the fascia, causing changes in range of motion. I'm always asking my patients to do different range of motion exercises when I'm assessing for chronic GVHD. I ask them to raise their arms straight above their head to see if they're able to do it. In chronic GVHD, when they go to raise their hands above their head, their elbows can't fully extend or their shoulders aren't able to extend completely. It could look like a goal post sign where the musculature is tight and doesn't allow for that range of motion.

You can see it in the shoulders, the elbows, the wrists, and the ankles. So we should make sure we're assessing patients in clinic completely, even for subtle signs like when a patient says, "I went to go reach for something from the top of the shelf, and I'm just not able to quite get it and it's really painful."

Jaime Shahan

One time I had a patient who said, "I haven't laid down on the floor for a really long time. And I noticed that when I did, I couldn't get my hands to hit the floor. They stopped right above me." The features are very distinctive. When I talk to my patients, I look and feel and actually pinch the skin. The elasticity of the skin is lost sometimes in these patients with chronic GVHD affecting the joints and subcutaneous tissues, and it can be somewhat subtle, like you said. The skin sometimes can start out a little thicker, like cookie dough, and then eventually, it can become very tight, almost like leather or even very firm like wood. So if you catch it early, it can be better. We try to tell our patients very clearly to be monitoring for those types of things.

Let's talk a little bit about the eyes. We don't really see ocular issues at all in our acute GVHD, right?

Diya Sabnani

No, but in chronic, we certainly do at times: usually it's dry eyes or keratoconjunctivitis. You generally want to get your patients plugged in with an ophthalmologist post-transplant so that they're having regular exams. These issues can go from mild, dry eyes all the way to where it feels gritty, like sandpaper. It's very debilitating, and it becomes difficult for them to even see.

Jaime Shahan

We have a lot of chronic GVHD patients that end up needing a scleral lens to protect their eyes from the air because they hurt so much. A lot of them are also using regular moisturizing eye drops.

When I first started practicing, we were using Schirmer's test to grade eye involvement. You would take a little piece of paper and put it on the patient's eye, and then you would see how much tearing there was on the paper and grade based on that. Obviously that's not a practical test, and it's very uncomfortable for patients, so we don't use that at all anymore. But tear production is still a way that we’re able to clarify what's going on with the eyes. Instead of using Schirmer's test, now we're just asking patients about how many times they're using eye drops, those kinds of things.

Diya Sabnani

Chronic GVHD can also affect the lungs. There's a couple different things that sometimes happen, but one of the diagnostic features of lung GVHD is bronchiolitis obliterans, as we mentioned before. Sometimes patients have a difficult time getting air out of their lungs because over time, the inflammation that's caused from the donor cells causes some scarring or loss of elasticity in the small airways.

Jaime Shahan

I tell my patients that their lungs are like trees upside down: The large airways are like the trunks, and the alveoli are the leaves. And basically, the elasticity of the alveoli is lost. Sometimes even the structure of the alveoli is completely demolished so air gets stuck in the bottom of the lungs. When you look at a CT scan, for instance, it looks like stained glass where the air gets stuck. It's black there, and then it's gray in other places where they've been able to exhale.

What are the symptoms that you see when patients have chronic GVHD affecting the lungs?

Diya Sabnani

Usually it starts with a mild change in shortness of breath. We try to gauge, is it just at rest? Is it just during moderate exercise? Or is it when you're walking from your front door to your mailbox and you're feeling short of breath? If you climb a set of stairs, did you feel short of breath after that?

Jaime Shahan

I sometimes will hear patients say that if they're singing, they can't get the air out; they can't fully project. And that's also something that's pretty subtle and can be difficult to pick up on at the beginning for sure. We have to really be proactive in monitoring them with pulmonary function testing.

Diya Sabnani

Yeah. When you're doing your pulmonary function testing, Jamie, what are you looking for changes in?

Jaime Shahan

The number 1 issue that you have is a loss of your expiratory volume, but also residual volume will be high. So we might have a decrease in the FEV1, but also a rise in the residual volume. You'll see that RV go above 100, for instance, because they are not fully able to get that air out and their residual volume is higher than expected. Sometimes they have a decrease in the forced vital capacity, the forced expiratory volume, but also then that increase in the residual volume.

Diya Sabnani

As we’ve discussed, while acute GVHD is usually in the liver, skin, and GI tract, chronic GVHD can manifest in many other organ systems. So it really is vital that we’re proactively monitoring our patients—even after the 100 day post-transplant mark—and educating them on what to look for and report to us.