Immunotherapy-Caused Pneumonitis: Identification and Treatment

Podcast Transcript

Respiratory Exchange Podcast

Host: Dan Culver, DO

Guests: Simon Mucha, MD and Mamoun Abdoh, MD

Immunotherapy-Caused Pneumonitis: Identification and Treatment

Raed Dweik, MD:

Hello and welcome to the Respiratory Exchange Podcast. I'm Raed Dweik, chairman of the Respiratory Institute at Cleveland Clinic. This podcast series of short digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease.

My colleagues and I will be interviewing experts about timely and timeless topics in the areas of pulmonary, critical care, sleep, infectious disease, and related disciplines. We will share information that will help you take better care of your patients today, as well as the patients of tomorrow. I hope you enjoy today's episode.

Dan Culver, DO:

Hello, my name is Dan Culver. I'm the Chair of the Department of Pulmonary Medicine at Cleveland Clinic. I'm the guest host today of this episode of Respiratory Exchange, the program designed to provide information on relevant topics and pulmonary and critical care medicine. I have two guests with me today, Dr. Mamoun Abdoh, who's one of the leaders in the thoracic oncology program and the Department of Pulmonary Medicine. Good morning, Mamoun.

Mamoun Abdoh, MD:

Good morning.

Dan Culver, DO:

And Dr. Simon Mucha, who directs the medical oncology ICU unit at the Cleveland Clinic.

Simon Mucha, MD:

Good morning.

Dan Culver, DO:

So today we're going to talk about immune checkpoint inhibitor toxicity and immune-related adverse reactions, kind of a new phenomenon. It didn't exist when I was in training, but we're seeing more and more of it now. I'm really happy the two of you're here to educate us about this.

Mamoun Abdoh, MD:

Thanks for having us.

Dan Culver, DO:

Simon, maybe I can start with you. What exactly is the immunology behind this? Why does inflammation happen and how would you define immune-related adverse events?

Simon Mucha, MD:

Yeah, so checkpoint inhibitors are a new group of cancer targeting therapies that are really different than your classical chemotherapy. So they do not really directly target the cancer cell and induce toxicity directly, but rather target pathways that have developed so that cancers can escape our normal immune response. So in a way, it's taking off the brakes from the immune system and allowing the immune system to have, you know, a more effective immune response.

Because this is not specifically targeted to a particular cell or particular surface protein on a particular cancer, some of these immune responses can be non-specific and can affect other organs other than the target cancer.

Dan Culver, DO:

So what are some of the common agents that are used now that people might have heard of?

Simon Mucha, MD:

So there's really two main pathways that are currently being targeted. One is the CTLA-4 inhibitors. You may have heard of ipilimumab as one of the earliest agents that was identified here. And then the program death, cell death pathway, which is either the targets the program, the cell death target itself, or its ligand PDL1 or PD1.

One of the agents that you might've heard of is, you know, pembrolizumab or nivolumab. More recently, there's a third pathway that's been identified, and it's been approved just last year for combination therapy in myeloma that targets another pathway called lag three, which is sort of a novel pathway that facilitates, or when it is not inhibited, can prevent CT cell exhaustion in T cells that are activated through these checkpoint inhibitors. So really multiple pathways that we can target to activate T cells that otherwise be inhibited by the tumor milieu that has a sort of an inhibitory signaling.

Dan Culver, DO:

So this all relies on the biology of immune surveillance that the immune system normally is eliminating cancerous and precancerous cells, and in cancer is no longer able to do that. So it's really unleashing the immune system. Is that a good way to think about it?

Simon Mucha, MD:

Absolutely.

Dan Culver, DO:

Okay. So when we unleash things, sometimes we get intended effects and sometimes we get some unintended effects. And certainly one of the big areas, especially in lung cancer that gets affected by these off target effects is, is the lung. That brings us to the concept of pneumonitis.

Mamoun, tell us a little bit about an immune checkpoint induced immune pneumonitis, what it looks like and, and how it happens.

Mamoun Abdoh, MD:

Yeah, absolutely. It's a very unique phenomena that, like Simon mentioned, when you unleash the immune system or take off the brakes, you are helping the immune system to fight the cancer. But at the same time, you get those side effects. That's are, we think it's immune-mediated, and when it happened in the lungs, it come in different forms and fashions. The most common one and recognized and label is pneumonitis, which is the non-specific inflammation in the lung in these patients.

It is a unique phenomena in multiple levels, although it has been reported to be rare and less than 5% of patients receiving immunotherapy, some report stock, it's even less. And in the real world it's probably a little bit more, it could be fatal in a subset of patients. And out of all people that get side effects out of immunotherapy, patients who die from this as a side effect, third of them are dealing with or dealt with pneumonitis.

So it's the most common fatal cause out of all patients receiving immunotherapy. So that is becoming, over time, where the use of immunotherapy kind of just being more common and this therapy being more applied into multiple types of cancers, including lung cancer and others, we're seeing more and more patients that are dealing with this phenomena. It seems like it, we still have a lot to learn about how this happened and why some patients develop this over time. We could allude into that later on, so.

Dan Culver, DO:

Yeah, lung cancer's definitely one of the risk factors for lung-related immune reactions. Are there other patient risk factors or therapy related risk factors that rise to the top of your mind that are important when we think about this happening?

Mamoun Abdoh, MD:

Yeah, this topic has been looked into in the literature in multiple ways. Most of the studies have been retrospective, looking at patients that received immunotherapy and see if they, what are the specific risk factors? And the first few that have been identified, like you stated, is if patients have lung cancer as opposed to other type of cancer, these patients have higher incidence of pneumonitis.

The other ones are, if you have a preexisting interstitial lung disease or interstitial lung abnormalities, prior treatment with radiation to the chest, and if combination therapy with immunotherapy have been used. So these are the most common and most highlighted in the literature. There have been a few others that is still probably more research will be needed is history of smoking, COPD, asthma and others. Those are the ones that have not been clearly linked, but seems to be kinda highlighted in those retrospective studies.

Dan Culver, DO:

And of course, this can present as a spectrum of disease from some incidental radiographic findings all the way to fulminant respiratory failure. Maybe we can start with the more severe end of it and work our way backwards. Simon, when you're in the ICU, what do you see, how do these present, how do you work through the differential and what kinds of patients are you seeing there?

Simon Mucha, MD:

Absolutely. Well, first off, I wanna say that severe toxicity is rare. We do see it more often because we treat a lot more patients and that's why it's important I think, for anyone who sees patients in the acute care setting. Fulminant toxicity can happen at any time, often happens in patients who've had experience some degree of toxicity previously, often mild and it can present with pneumonitis with p and respiratory failure.

But what we often see in grade three or four, sort of, the severe toxicity requires hospitalization, is there's often an overlap where inflammation really affects multiple organ systems. So in the acute care setting, especially in the ICU, we often see multi-organ dysfunction. Pneumonitis is one of the more common presentations.

So respiratory failure, which we will have to differentiate from other causes of respiratory failure, is the someone who has tumor progression with lymph venge spread and is therefore hypoxic and has new infiltrates. Whereas the someone who has, you know, an infection bacterial viral or is this someone who's been on maybe a course of steroids for a prior adverse event, has been therefore immune suppressed?

Is this an atypical infection in someone who's now at risk for other infections? So the challenge in the ICU or any acute care setting is really that symptoms are often vague. Any organ system can be affected. It is a diagnosis of exclusion. So we really have to work out if there's any other diagnosis. The most common etiology or the most common differentials that we would think of is usually I would say cancer progression or infection in the acute care setting.

I would also add that thrombosis risk is probably top on the differential because these patients are at an increased risk for thrombotic events, both from their underlying malignancy and the inflammatory process that gets unleashed by these checkpoint inhibitors.

So those are really the differentials. And the key here is just to really recognize that really any patient that presents with, you know, an acute change in their medical status to have any new organ dysfunction, even if it is vague, to consider checkpoint inhibitor toxicity or an immune response to their treatment.

And then it is a matter of collaborating with the oncologist, the mol, the pulmonologist, the hepatologist and gastroenterologist, whatever organ system may be involved to really rule out potential other causes for their symptoms and identify checkpoint toxicity early if this is the case so we can treat it.

Dan Culver, DO:

You mentioned that other organs, a lot of times you see those involved as well. Can you elaborate on that? Which ones do you see most commonly?

Simon Mucha, MD:

Yeah, so it's interesting for the most commonly affected organs are probably the gastrointestinal systems. So colitis, hepatitis, the lung pneumonitis is common, skin and musculoskeletal systems as well as the endocrine system. But it really can run the gamut. And what is important is that some of the more rarely affected systems are probably the ones who have overall the worst outcome for two reasons.

One, we’re not as familiar with it. I think our pulmonology colleagues are by now very familiar that pneumonitis is a true common side effect of checkpoint inhibitors and we watch out for, but we may miss a subtle myocarditis that presents with elevated cardiac markers that if you don't think to check it may go unnoticed, or just some arrhythmias, some subtle neurologic changes. Myasthenia or other myositis can have profound effects and if recognized late can have severe outcomes.

Dan Culver, DO:

So this is really a whole body thing. We really have to be quite in a Sherlock Holmes mode when these things come in.

Simon Mucha, MD:

Yeah, when we talk about this in conferences, we always say, I mean, we laugh about it, but anything you can attach an “-it is” to can be affected by checkpoint toxicity from head to toe. Anything with-

Dan Culver, DO:

So penitis.

Simon Mucha, MD:

Penitis.

Dan Culver, DO:

Okay, a new diagnosis invented here. Mamoun, is that what you see also in the outpatient setting? There's a grading system of course, and many of the outpatients will have the milder grades. Is that the same sort of thing you think about as a patient presents to you? What kinds of ways do the patients typically present?

Mamoun Abdoh, MD:

So yeah, that's a really good question. The symptoms when it comes to pneumonitis and lung involvement are pretty broad, pretty nonspecific. So most patients will have some degree of dyspnea. Cough is pretty common, tend to be dry. Some people may have fever and less commonly it may be associated with chest pain.

So, a good portion of patients may present with very mild symptoms, while others a good, another one, especially with grade one, are asymptomatic, it's just a radiologic finding you catch on a CT scan. And the challenge with these is that patients, although we have a grading system for this from one to four or five, which is the fatal one, is that patients don't have to stick with the same grade and they may start as a grade one and then evolve into grade two or three.

So, it's very important to kind of catch these things and recognize it early and continue to follow these patients over time. And like Simon mentioned, the challenge with the diagnosis is that it's always a diagnosis of exclusion.

So, when you treat these patients, when patients are receiving immunotherapy, there is always the concern with their malignancy, is this a progression of for their lung cancer or is this the other odd phenomenon that you see with, with immunotherapy like pseudoprogression where things get worse before it get better. And although it's a rare thing, it confused the clinician. Is this a progression of the disease? Is this pneumonitis? Is this an infection?

So, you're gonna go into that journey, figure out what exactly going on with this patient and follow them closely. The other thing that has been reported in the literature and has been rarely seen is the hyper progression where patients start on immunotherapy and the disease, their cancer can just get way out of control and, and it progress even further. So those are the things that always kind of come to our mind along with infection and other side effects and other adverse events that is associated with immunotherapy.

And out of the reported cases with pneumonitis, it looks like more than 50% of patients with pneumonitis have other- itis that is going on somewhere in the body. So it's always gonna be vigilant and making sure that you are looking at the patient as a whole as opposed to focusing only on the lung problem.

Dan Culver, DO:

So, this brings up a thing I think we all wrestle with, which is diagnostic testing versus empiricism. I'm curious to hear from both of you about how you balance that. When do you do a bronchoscopy, what's the role for observation? When do you think about stopping the drug? How often do you just put some empiric therapy on board? That's always challenging, but I'd like to hear your philosophies on that.

Mamoun Abdoh, MD:

If I may start. I think when, when it comes to the treatment, empiric treatment versus further investigations, I think if you have the appropriate clinical scenario and you kinda looked into the differential that we talked about earlier and your suspicion of pneumonitis is kind of high on the list after all of that, based on the CT findings, the symptoms and the history and physical, at that point, you really wanna consider holding immunotherapy at least because this is the mainstay treatment and that is a collaboration between the pulmonologist or the intensivist and the treating oncologist because it's quite important.

This is to some extent is a very, very important treatment to this patient. And holding it may have consequences on their, on their outcome and survival. So you think of that real, you think of it heavily before you pursue it, but once you are concerned about pneumonitis, you really wanna hold treatment.

The question about starting steroids, it is a little bit of a matter of collaboration with oncologists and figure out how symptomatic is the patient when they are asymptomatic or when they are in grade one. Holding treatment might be enough and just close follow up, it may be every few days or every week or so will become very important to kinda see if this patient progress from grade one to two or three.

When they are really sick it's a whole different matter and I'm gonna hand off the mic to Simon to elaborate on this, but this is where probably sitting and waiting become more costly and you gotta do something, so.

Simon Mucha, MD:

Yeah, really challenging. And I just wanna pick up two things that I think you mentioned as a, I think it's depends how the patient is doing and collaboration between everyone involved. I think we're all want to do something when someone comes in with potentially life-threatening toxicity, but if it's an infection that we treat with high dose steroids, we certainly are doing the wrong thing for the patient. So yeah, you have to be reasonably confident that you've ruled out other etiologies as best as you can.

And then together as a group with everyone involved, the intensivist, the oncologist and whatever's, you know, other organs are involved, you know, bring the team together and, and it's a, you know, joint decision of, you know, how confident are we, how scared are we that this is, you know, a potential toxicity? And oftentimes, you know, when we feel like we've had 24, 48 hours of workup, our immediate infectious workup is not positive.

We may or may not have an opportunity to biopsy organs that could be affected with cancer progression. And then if the patient's you know, life is in danger, organ function is in danger. I think empirically treating with steroids, which in this case if you have a significant organ dysfunction would be your first line. Treatment of choice is often what we go to. And then try to, like you said, monitor response very closely.

Sometimes steroids alone are not enough, and that's the next challenge is if the patient does not immediately improve, is this failure of therapy or is it the wrong diagnosis? This is, again, challenging to make the decision. Was I right or was I not? But this is again, something that I think we're very fortunate to be able to collaborate with folks who are familiar with us who see this a lot and I think the collaboration with multiple experts is, is key here. And really early, early on.

Dan Culver, DO:

Think about it early. How helpful have CT features and how helpful have bronchoscopy been for you in working through this?

Simon Mucha, MD:

In the ICU it's very challenging because oftentimes the patient is exactly the kind of patient that you would love the bronch, but you cannot because they're right on the edge of either requiring intubation or the risk benefit may not be there. Especially since, you know, there's not a, you know, a single diagnostic test that says this is or is not pneumonitis from checkpoint inhibitor similar with CT, but I think that's probably similar in the outpatient setting where you have a little bit more time to, to look at it more closely.

Mamoun Abdoh, MD:

Yeah, absolutely. I think if you look at the CT findings, they are quite nonspecific and they, they cannot really differentiate is this in, in a lot of cases, if this is related to infection or disease progression. I think the, the key when it comes to looking at the CAT scan is the findings that you are able to, to kind of just decipher out of reading that study and comparing it to prior tumor progression tend to be in the same, same side where the tumor started and then progress into that area or prior lesions that progressed over time infection might not be only unilateral, but the acute features of the patient when you see them tend to sway you in their direction or not.

The response to antibiotics, which is an easy attempt early on, cannot also help you with that. When you look at where, what the CT features of pneumonitis specifically, it looks like a lot of ground of glass opacities.

It could be bilateral, it could be only on one side and the, the organizing pneumonia kind of presentation where it's more consolidative opacities and the lower lobes with or without a ground of glass associated with it seems to be the most common. There have been a few attempts in, in multiple bodies in the scientific societies trying to figure out how we could group these into more of an acute presentation when they are really sick in the ICU and their CAT scan is more like diffuse elbow damage or it's a subacute presentation where you would think of organizing pneumonia being the most common and then, uh, less, less acute or more chronic kind of phase where you think of NSIP and, and HP being part of that.

But the key is that a lot of these classifications fail to include all patients. So you always see in these, in these cohorts where probably one third of patients are unclassified and it could be anything. And the other challenge is the CAT scan features does not correlate with how sick the patient and what's their grading system. So that's another, or their response to therapy. So that's become more of a kinda multifold problem.

But that is, I, I think the, back to what Simon mentioned, it's close follow up, respond to treatment and follow up on these CAT scan changes along with the clinical response. And in the outpatient setting, it seems to be that out of all the testing we do in our clinic, oximetry with ambulation seems to be the most helpful to kinda see how these patient progress, did they develop it while they were on treatment, did it improve with time? And you could repeat that frequently enough and join it with your evaluation and assessment of the patient to kind of decide if they are moving in the right direction or not.

Now when it comes to bronchoscopy, I think in the outpatient setting we have a better window to do it, but again, these patients are sick and the role of bronchoscopy ends up being to help with the diagnosis of exclusion, making sure that this is not an infection, this is not a tumor progression. Those seems to be the key things to rule out, but there are no specific findings on the lavage to kind of guide you, oh, this is pneumonitis.

Or even in some cases where we put patients through transbronchial biopsies, the findings on the biopsy are just lymphocytic infiltrates, which is very nonspecific in some cases, it could be with a granulomatous inflammation or it could be a nonspecific organizing pneumonia features. But what you are looking for when you do the transplanter biopsy is this tumor progression and that will probably be the most important piece of information you get from putting patients through it.

So over time, in the early cases of pneumonitis, we're doing more bronchoscopies, we're trying to put every patient through this and as time progress and seeing how these patients respond to withholding immunotherapy and the steroid treatment, we tend to kind of just narrow the group of patients that we do bronchoscopy for to the one that do not respond to the initial treatment.

Now the value of bronchoscopy gets a little bit higher at the same time they are sicker. So you're in a way the risk and benefit and decide.

Dan Culver, DO:

So we're learning maybe to be more parsimonious with that test. So you mentioned before Simon, that when you don't have a good response to steroids that there may be some other therapies. Which therapies do you think are the most beneficial in patients who don't respond to stopping the immunotherapy and maybe some initial courses of steroids?

Simon Mucha, MD:

I mean, the go-to, is corticosteroids and after that it's a wide open field. I mean a range of immune suppression from B-cell targeting agent like rituximab, maybe some infliximab, other immune suppression, cyclosporine, MMF. It really depends a little bit on the organ system that's involved. We use IVIG at times when we feel like there's truly an antibody mediated process. Right now we have a patient in the ICU who has myositis and myastheniagravis that's receiving a plasma exchange for the myasthenia. So it really depends on the underlying process and there's some nuance to this also what organ systems are involved.

For instance, infliximab is relatively contraindicated if you have coinciding hepatitis because it could potentially worsen outcomes there. So it's very nuanced and there is no, no real script of how to really proceed. So again, highlighting the need for really a multidisciplinary discussion with thoughtful considerations of risks and benefits at the involved organs.

Dan Culver, DO:

And the data right now, as far as I understand it, are still case series.

Simon Mucha, MD:

It's mostly case series and retrospective expert opinion. Yeah.

Dan Culver, DO:

Yeah. Any other different perspective on non-steroid therapies Mamoun?

Mamoun Abdoh, MD:

It is very challenging. I think we are trying to extrapolate dealing with pneumonitis and treating patients that are steroid resistant and use the data from the other type of inflammatory response that happened in the body and used that same data to see if it helped with pneumonitis.

And in the early studies in the early case series that used infliximab, it was extrapolated from the response to colitis. So, and it hasn't been a promising or even reassuring in this setting. Part of the challenge is, number one, we don't know why patients develop pneumonitis. We don't know why these patients don't respond to steroids and what dose of steroid, how high is enough.

And while you are dealing with the response or their lack of you are searching for another agent, they're gonna suppress the immune system and put them at higher risk, which is what some of these reports in the literature talk about. When these patients kind of just become steroid refractory, they die from sepsis, pseudomonas infection. Is it really the steroids or the immunosuppressant that you used or is it just the progression of the disease itself? And that's what we still don't have a good answer.

I think it, trying to think of it in multiple levels is very helpful. Based on the earlier records or early reports of infliximab, I'm a little bit shy of using it and I try to think of plasma exchange or IVIG as probably more promising, but probably more research need to be done in that field. When we are dealing in the outpatient setting, we have been using mycophenolate to see if this decreased the risk and, and decreases the patient's need for steroid.

But those ones are in the patient that are steroid dependent in the chronic form. So you put them on steroids, they get better, you taper them down and then you get rebound or recurrence of pneumonitis. And then once this kind of just battle back and forth extend beyond three months or so, we start thinking about steroid-sparing agents.

As Simon mentioned, more research, it will be needed in this setting. And, and the key is the collaboration with others.

Dan Culver, DO:

Yeah, I think you both pointed out a couple important themes. Early days here we're still learning really the pathophysiology, the best approach to diagnosis and management and, and the importance of working together is teams, which I think you both are a part of important teams that are doing that.

So I think this is an area to stay tuned to and I'm sure there will be more coming out every month and every year in the area. Simon, any parting thoughts? Anything that we missed that you wanna share with the audience?

Simon Mucha, MD:

Yeah, I mean, like you said, I think it's important, right? I think more than a third of all new diagnosis of cancers probably qualify for the treatment with checkpoint inhibitors. So no matter where you work, you will see a patient on a checkpoint inhibitor and toxicity, if there is a new problem, should be any differential. I think the other thing that we wanna stress is, yeah, I see them in the ICU, Mamoun sees them, you know, in clinic and in follow-up and we talk a lot about severe cases.

A lot of cases are mild, many cases respond well to therapy and many patients can continue on checkpoint inhibitor therapy after they've had treatment for their initial toxicity. So I think there’s a lot coming down a road in terms of the number of patients that we see and there's a lot to learn, but I think the future is pretty bright. I think as we learn to get better at treating it, as long as you recognize it early and treat early, I think patients can continue to benefit from this therapy, it was really advanced cancer care dramatically.

Dan Culver, DO:

Thank you. Any final words of wisdom Mamoun?

Mamoun Abdoh, MD:

I think I echo what Simon mentioned. It is immunotherapy is here to stay, it is changing the management of cancer throughout the field and we are gonna see more and more of these adverse events and the better we get in managing them, patients could continue on that path of therapy and get better outcome and better survival. So collaborate with your oncologist, get familiar with it, and don't be shy to ask for help.

Dan Culver, DO:

I want to thank both of you for your insights today. This is a field that's complex and moving very quickly, so it's great to have two experts like this discussing with this. Today I've been pleased to host this episode of Respiratory Exchange. Again, I'm Dan Culver at the Cleveland Clinic. We've had Dr. Simon Mucha and Dr. Mamoun Abdoh with us as guests today. And thank you all. I hope you enjoyed this episode.

Simon Mucha, MD:

Thank you.

Mamoun Abdoh, MD:

Thank you very much.

Raed Dweik, MD:

Thank you for listening to this episode of the Respiratory Exchange Podcast. For more stories and information from the Cleveland Clinic Respiratory Institute, you can follow me on Twitter @RaedDweikMD.