RSV in Transplant/Immunocompromised Population

Dr. Raed Dweik:

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.

Dr. Steven Gordon:

Well, welcome, everyone. My name is Steve Gordon. I'm Chairman of the Department of Infectious Disease and we have another chapter here on immunization vaccine with a focus on RSV. It's a pleasure for me to introduce two wonderful colleagues. The first is my longtime colleague, Dr. Christine Koval. Christine leads our adult transplant infectious disease, what we call delta group, and does so marvelously. And the other colleague is obviously Dr. Blanca Gonzalez. She also heads up the immunocompromised transplant section in the pediatric department here at the Cleveland Clinic. So, welcome to you both. Christine, I wonder if you could just tell the group a little bit about your background.

Dr. Christine Koval:

So, I am bred into the immunocompromised host portion of infectious disease. I started my career in HIV medicine and HIV care. In the era when lots of HIV infected patients were admitted for opportunistic infections. And given that experience, I managed to change gears a little bit and move to the transplant infectious disease arena, where I have enjoyed all of my experience and colleagues taking care of particularly immunocompromised patients with organ transplants and stem cell transplants.

Dr. Steven Gordon:

Well, thank you for that, and your wealth of experience we're going to continue to explore. On the pediatric side, we have Dr. Blanca Gonzalez. And Blanca, I wonder if you can give the audience just a little bit about your background.

Dr. Blanca Gonzalez:

So, I also shifted gears a little bit once I arrived to the Cleveland Clinic. Before, I used to do infection prevention. I had always loved working with immunocompromised, the opportunity presented itself for me to really shift gears and work more with transplant. And so, I did, and I found a lot of collegiality with my adult colleagues who have really helped me along the way and held my hand as I was learning more about transplant.

Dr. Steven Gordon:

Wow. Well, thank you so much for that. And your synergies I know crossover in clinical care and it's a such strong powerful group here, which we're all fortunate, as well as our patients. I want to start by pivoting. The term immunosuppressed, immunocompromised, what that means. There are estimates as I look into the literature that maybe 3% of the US population is immunocompromised. Obviously, that depends on a bucket. There was a recent survey in JAMA, delivered the patients where maybe their estimates are even double that depending on how you define that cancer, monoclonal antibody. But I wonder, Dr. Koval, if you can tell us how you assess immunocompromised patients in terms of the different buckets, the most common things that people may fall into.

Dr. Christine Koval:

Yes. So, it turns out that immunocompromised, the immunocompromised bucket is a widely disparate group of individuals; and classically, we think of them as our stem cell transplant recipients, our solid organ transplant recipients. And, more recently, with the introduction of several more novel immunosuppressants, we have expanded our consideration of immunocompromised hosts. Now, they're not all immunocompromised equally. So, for example, a patient who's on a TNF alpha inhibitor would be immunosuppressed in a much different way than somebody who's receiving CAR T therapy, for example, for treatment of a lymphoma or leukemia.

So, shifting just a little bit to how RSV might be considered, patient on TNF alpha inhibitors would not be at any increased risk for RSV, severe RSV infection and may just have a more typical RSV type of upper respiratory infection. And then, our stem cell transplant recipients, depending on specific risk factors even within that group would be, potentially, at very high risk for catastrophic RSV infection.

So, we think about these differently depending on the type of immunosuppressant, their underlying disease state. And then you add on those, onto that, the additional risk with age and underlying comorbidities like structural lung disease or inflammatory lung diseases, diabetes, renal dysfunction. So, it is a very disparate group of people, and it does require some emerging expertise.

Dr. Steven Gordon:

Well, thank you for that. It is, as you said, complicated and evolving. Blanca, I wonder if before we get into pharmacologic interventions, including vaccines and medicine, as a pediatrician, obviously you're used to the concept of cocooning, and that emerged, I think, with the pandemic, as well. I wonder if you could explain to the audience what that means in terms of a non-pharmacologic intervention in protecting potentially a newborn, but also translating that to potentially elderly patients, as well.

Dr. Blanca Gonzalez:

So, I think that the concept of cocooning really took off with the vaccination of pregnant women for pertussis. So, getting that Tdap vaccine protects the infant, and that was where the concept of cocooning really happened. And now with the new vaccine approved for mothers between 32 and 36 weeks of pregnancy. If you give the vaccine greater than 14 days before delivery, the maternal transfer of antibodies will protect that child for a period of time, where they're more vulnerable because for us an infant is really an immunocompromised host, as well, until that immune system starts really developing. So, we thought always of contact precautions for RSV. And most recently, today I was looking at AAP Red Book, changed the recommendations from contact to contact and droplet. And preventing that very close contact, it's hard to do within a family, not have little ones interact with their siblings who are the ones who probably bring all these infections home. But really, hygiene, limiting that face-to-face contact where droplets could be inhaled by these kids. The real cocooning strategies, I think we're seeing with vaccination of mothers, and the use of these passive monoclonal antibodies in children.

Dr. Steven Gordon:

Sticking with the pediatric side because, as you've taught us, the most common cause of hospitalization for the newborns or neonates during that first year is RSV. But give us that picture. Having had kids with croup and being hospitalized, you as a clinician, can you give us that picture of the morbidity and the mortality that you see.

Dr. Blanca Gonzalez:

It is funny that you ask me that because although, yes, the incident of hospitalization in pediatrics, but, if you compare numbers of pediatric to adults, how different, I would say, that RSV is a disease of the elderly. When you compare the numbers, you are looking at maybe 50 to 100 thousand admissions for kids with RSV each season. Compare that to more than 150,000 for elderly adults. And then we have deaths in the rate of 100 to 300 versus more than 1000 every year for elderly.

So, even though we always think of RSV in the pediatric population, probably the heaviest hit is the elderly population. But, seeing kids, we do see every winter our share of children with RSV and the symptoms can vary from very mild disease, just an upper respiratory tract infection to those who develop bronchiolitis and pneumonia in which they can have prolonged hospitalizations since the care is really supportive.

Dr. Steven Gordon:

Thank you. Dr. Koval, if I could pivot back to you in terms of when we did the pharmacologic prevention, when you've been a leader, pioneer in getting patients who are being considered for transplant, to get that vaccine or that assessment. Can you tell us a little bit about what goes on in that situation to try to get those patients where you may be able to do something for prevention, whether it's medication or vaccine, before their transplant?

Dr. Christine Koval:

So, yes. Specifically for solid organ transplant it’s a little bit different for the stem cell transplant patients where you're wiping out that existing immunity and may not need to give a lot pre-transplant. But for solid organ transplant candidates, we do strongly recommend that if vaccines are going to be done, and we recommend a list of adult vaccine recommendations, that they be done before transplant. Because after transplant, there is a wealth of literature on inadequate humeral responses, inadequate T-cell responses, and those immune responses, while they may change through the course of the post-transplant life, may never reach normal, and ordinarily do not reach normal.

So, they may respond but they will often respond sub-optimally, and as we saw with COVID vaccination and has also been shown for influenza vaccination, additional doses or higher doses may be required to achieve somewhat similar antibody responses. Now, antibody response doesn't always mean complete protection. There may be underlying T-cell responses that are more difficult to measure and may provide substantial protection from the more serious manifestations of the disease. But we do want to optimize vaccines. And we think that giving them before transplantation is a much better option than waiting until afterwards.

And there may be strong considerations, depending on the type of organ, that the patient is going to be receiving. For example, a lung transplant recipient, we really want them to be vaccinated against microbes that are going to infect that lung. So, we really put pressure on them to get their influenza vaccines, their COVID vaccines, their pneumococcal vaccines. And now, with the new RSV vaccine, we think it's a good opportunity pre-transplant to protect them from RSV post-transplant.

Dr. Steven Gordon:

Thank you. That raises another question that I wonder if you could talk about, and that's the concept of vaccine hesitancy in terms of explaining to patients. So, I think the transplant patients are going to be quite motivated, I would think. We could talk about strongly recommended versus mandatory in that population, but I wonder if you could talk about some of your strategies in terms of now approaching the parents for the kids, or approaching the patients in terms of persuasion, in terms of the value concept of vaccination.

Dr. Blanca Gonzalez:

Okay, so first, it's important to clarify that the new RSV vaccine, which is different to monoclonal antibodies, in its current state is not a vaccine that is being trialed right now in pediatrics. I think there's deja vu from the 1960s, there was a formalin vaccine that, unfortunately, enhanced the effect of RSV in children and during the trials, two children died. And so that vaccine, I think in everybody's mind, and for the longest time, this was in everybody's mind. So, finally they were able to stabilize that F protein so that it wouldn't fold and then you could target the pre-fusion form. And that was what finally led to this new vaccine. But this vaccine is not being trialed.

There's an mRNA vaccine that is currently in trials for 2 to 17. We don't have data for that yet. But in a general sense, I think one of the things that we do explain to our parents is, children who are undergoing transplant, especially the solid organ transplant, is that you're receiving a precious organ. An organ that in some cases, like in the case of heart transplants, another child dies so that your child can live. When we have vaccine preventable diseases, it would be very unfortunate to lose a child and the graft because of not vaccination. And so, that is one of the things we usually do, and we do a lot of work trying to tackle vaccine hesitancy. For the most part, sometimes there are vaccines that are mandated, that we require to transplant some of our patients. And so, I think there's a lot of conversations with parents are needed to overcome that vaccine hesitancy. So, we try to get as much done as possible before the transplant. Because once patients agreed, we know that opportunities later may or may not be available.

Dr. Steven Gordon:

Christine, I wonder if you can expound on that in terms of the other risks that you take into account and trying to also convince household members of the importance of vaccination. Because as you said, some of these vaccines may not be as efficacious for a variety of reasons, but we know that the household contacts are going to be the biggest risk for exposures for most of our patients.

Dr. Christine Koval:

Yes, when we talk to patients about their risk for infection after transplant, be it stem cell transplant or solid organ transplant, we emphasize the need to incorporate a lot of safe living practices, and that includes what Dr. Gonzalez has alluded to. The hand hygiene, minimizing close exposure to obviously ill people or people with upper respiratory tract infections. And even with young children, children younger than five years of age, your grandchild, your niece, your nephew. They may look fine, but they may be carrying the virus before it's symptomatic and we would recommend that during respiratory virus season, that maybe they aren't volunteering to babysit those kids or letting them crawl on them and kiss them. Maybe, just start planning the strategy to minimize that effect of spread of viruses. But that also includes emphasizing that a wall of protection from vaccination may also be a benefit for the recipient of that transplant.

So, most of the caretakers and every transplant patient needs a close care partner, most caretakers understand that they could pass along an infection to that transplant recipient. And most people understand that they don't want to be that person. So, vaccine preventable illnesses are one group of infections that there's some control over. Not every infection is controllable by that care partner but to prevent yourself from being infected is a key opportunity.

Dr. Steven Gordon:

Thank you for that. Dr. Gonzalez, I wonder if we can talk about your recommendation about masking for these patients, releasing that masking can turn into a four letter word. But even before the pandemic, we saw immunosuppressed patients going through the hospital wearing some facial protection and for a lot of good reasons. I wonder, what's your advice to your patients about masking?

Dr. Blanca Gonzalez:

In the community?

Dr. Steven Gordon:

Yes.

Dr. Blanca Gonzalez:

Prior to COVID, when they had done studies looking at masking, most of the benefit was for patients who were with influenza and in patients who were immunocompromised and within the household. So, other than that, it was not well-documented. And still, I don't know that after influenza, I mean after COVID, that the effect of masking was ... there were some studies that done, looking at, you know, that after masking, you did see a drop in certain populations. But well controlled studies are not easy to do when you are looking at masking. But I think it offers an additional layer of protection. For example, for us pediatricians who constantly get coughed in the face, this is like a daily happening. So, even though RSV technically is contact, and initially the isolation precautions for contact, we are always like, "well, maybe during respiratory season, we wear our masks," just because that additional exposure sometimes can happen to us. Especially in children who are coughing because close contact to examine them will always result in some additional exposure that we didn't know.

But for our transplant patients, what I do tell them always, like Dr. Koval, I emphasize do not be afraid of telling people who are sick that you don't want them in your house. Because I think that is the most important thing. There are some things that you can't prevent, which is another sibling bringing an infection, and you're not going to mask everybody at home. But sometimes, if there's somebody who they know they're sick, they know and they either mask the child or isolate the sick person, into another room. I think that the mask protection is more in the case of RSV, because those droplets can come in and infect somebody else.

Dr. Steven Gordon:

Thank you. Dr. Koval, if could switch to testing and the reasons for testing and how you approach testing in your immunosuppressed patients, with the concept being that some of these things, earlier detection could lead to potential treatment when we have treatment. Let's focus on that URI. I'm certain that's smart enough to distinguish if someone's got influenza, para-influenza, SARS-CoV-2. What is your practice for these patients in terms of thresholds for testing, types of testing during respiratory viral season or beyond?

Dr. Christine Koval:

Well, certainly the highest risk individuals, those stem cell transplant patients who are early post-transplant, who are treated for graft versus host disease, who have low lymphocyte counts, who had an allogeneic transplant with mild ablative conditioning. Those patients, you barely need a sniffle before you're going to test that person for a variety of respiratory virus pathogens. Not all of them. In fact, most of them do not have a treatment, but the ones that do require early treatment, because once those infections travel from the upper respiratory tract to the lower respiratory tract, the horse is out of the barn, and we often can't do anything. So, for our highest risk individuals, those allogeneic stem cell transplants with mild ablative conditioning, fairly early after transplant, low lymphocyte counts, low white blood cell counts, those patients need early diagnostics, early identification, particularly for RSV, particularly for influenza.

For RSV in particular, we would administer ribavirin very early, with the intention that we prevent progression from upper tract to lower tract disease. There is no randomized control trials of this, but there are retrospective studies that demonstrate that any ribavirin product in these patients will prevent progression from upper tract to lower tract disease and will reduce mortality. So, that is our standard practice. There may be some adjunctive immune regulators like IVIG. It used to be that steroids were administered. Not so much anymore, but IVIG, particularly if it's advancing to the lower tract.

So, early diagnostics, very important in certain subsets of the population. Similarly for our lung transplant recipients. We want to identify those patients because once they have that RSV for several days, that allograft is going to get triggered, and there's going to be inflammation. And there will likely be subsequent effects on allograft function. So, over time, that initial trigger from the respiratory virus results in an alloimmune response that affects chronic lung allograft disfunction, also called CLAD. So, there's an intention to treat, treat early, and to treat with coincidence steroids to sort of abrogate that immunologic response down the road.

Dr. Blanca Gonzalez:

Yes, in pediatrics, the data, similarly we know that ribavirin in normal host, in normal children does not work. We know steroids, also do not work, and that the mainstay of pediatric in normal host is supportive. Now, for transplant patients, for patients with inborn errors of immunity. Sometimes what we know that the risk factor, again, all comes to the progression of upper respiratory tract to lower respiratory tract infection. So, we know that risk factors for progression, are lymphopenia, so having lymphopenia is a risk factor. Other things that they've seen in children aged less than two, having co-infections with other viruses, which is not uncommon in pediatrics. And, having other bacteria, those are things that have been associated with progression to lower respiratory tract infection. But, if you ask 10 different centers and their studies about this, they all use different strategies, because there are centers that have had good outcomes not using ribavirin, and there are some that combine it with IVIG, so the data is all over the place. So, it's really individualized, too. And again, it's the inhaled one, that is only FDA approved for the treatment of RSV.

The other thing is that with our immunocompromised patients, when we talk about testing, one thing that's a little complicated, is these patients can shed the virus for a very long time. And sometimes that buys them isolation periods that are very prolonged because with more molecular testing, we are detecting probably residual virus, but we can't distinguish if this is going to be transmittable or not. So, unfortunately, some of our patients are on isolation for a very long time because they will repeatedly test positive.

Dr. Steven Gordon:

So, Dr. Koval taught us that in terms of the same thing with SARS-CoV-2, especially with patients on rituximab. They can be positive for a long time. Christine, I'm wondering, in terms of strategies, obviously we don't have a mAB, a passive mAB for every pathogen, but do you see a point where for some of these patients where you know it's going to be very difficult to get an effective immune response, do you see that strategy will continue to proliferate for some of these patients?

Dr. Christine Koval:

I think for a very small subset of patients that may be what we're looking at. And for some, it's going to be a short-lived thing. For others, particularly those with lymphomas, B-cell lymphomas on multiple therapies, who are also getting B-cell depletion, those patients have multiple arms of the immune system that are being affected, and that loss of B-cell and production of antibodies to protect the mucosa from initial infection will be a problem for repeated infections. But there is also that potential for this disorganized, dysregulated immune response that can result in more severe inflammatory manifestations in the lung resulting in respiratory failure and potentially even death.

So, as we see more mixed infection, mixed immunosuppressants used on more complicated regimens, I think trying to decipher which of these patients are going to benefit from something like a monoclonal antibody, is going to be more and more owner some. But I do think that there will be a potential role, if studies bear it out, certainly not something that can be used currently. It's not ready for prime time, but there has been an interest, for example, in stem cell transplant units during respiratory virus season when there's an outbreak. Now, all of the infection prevention strategies go into effect. Your know, masking, gowning, gloving, distancing, all those things to prevent transmission from one individual to another.

But potentially, and has been of interest in the past, is to provide a monoclonal to protect those people during that high-risk period early after the stem cell transplant. So, that could be something down the road that if it bears out in clinical trials, would be something that may be of interest and of value.

Dr. Steven Gordon:

You know, before I want to just switch to another topic, I want to highlight your courageousness but also your patient-centered approach in terms of, that you view all these patients who maybe need transplants as, there's no such thing as a free lunch. You teach us that by net state of immunosuppression and the risk. But I wonder if you could walk through what now turns out to be, looks very common-sense but at the time was maybe somewhat controversial, is that your leadership with your colleagues in the renal transplant during COVID, about accepting SARS-CoV-2 deceased donors for certain transplants.

Dr. Christine Koval:

Yes. For most transplants, that appears to be an effective practice is to transplant organs that are non-lung organs, extrapulmonary organs because, as has been observed from many and most RNE respiratory viruses is they don't infect other organs. They're not transmissible through the blood supply, they're not transmissible through organ transplantation, and before any logical data came out from- from pathologists or basic scientists, the writing was on the wall that there was not likely to be transmission from extrapulmonary organs. So, viewing the clinical landscape I think carries its own weight in the absence of having robust pathologic data. And I know that for SARS-CoV-2, the number of patients that benefited from receiving kidneys from SARS-CoV-2 infected donors was great. There were several hundred individuals who benefited from those organs.

Dr. Steven Gordon:

Well, thank you for your leadership on that. I know at the time; it was not necessarily easy because there's always going to be a counterfactual or people that will tell you about abundance of caution and things. But thank you. Blanca, anything else that you want to add in terms of, as we look to the future in that make you optimistic or maybe things that are making you nervous.

Dr. Blanca Gonzalez:

I think that the development of a novel or a new monoclonal that targets that pre-fusion is the word, and you know it really changed the field because we used to use palivizumab, which had to be a monthly infusion. It was five infusions starting at the beginning of the RSV season. And it was, quite expensive, as well. So now that you have that you can just use one administration at the beginning of the RSV season, because targeting that pre-fusion, the half-life, went up to 71 days. So now you have something that can last the whole season. And very interestingly, we now are recommending this not for only the first RSV season for those who are younger than eight months of age, but for the second RSV season for those who are 18 to high-risk individuals, from 8 to 19 months for their RSV season. And that includes some of our immunocompromised children, as well. So, potentially we have children who are transplanted at very young age, for example, our livers, kidneys, and hearts. Even though this has not been studied in this population, it's something that you can see maybe could come in the future, as well.

Dr. Steven Gordon:

Thank you. Dr. Koval, anything else in terms of making you nervous or making you optimistic?

Dr. Christine Koval:

I'm optimistic. I mean, in general, RSV is not a catastrophic infection, even in the immunocompromised overall population. It is small subsets of individuals that really run into trouble, and those people need to be on alert during respiratory virus season. They should know when RSV comes, they should know when RSV goes, in their community. They should know how easy it is to be transmitted from young children. They need to be aware of this. And I do think it's really important to stress, because Dr. Gonzalez has a different prism of RSV, you know, she's got her very young humans who haven't developed their immune system yet. But afterwards, those kids do great with infections like RSV. They're training their immune system, they have a strong adaptive response to these things, and they clear it.

So, what's important to note about us old folks, is that we lose coordination. We lose coordination in a lot of ways, but we also lose coordination from our immune system. So, as we get older, we can't coordinate the adaptive response to the virus in the lower airway, and particularly RSV, but other viruses. And we can't turn off the immunologic response as well. So, our adaptive responses, our T-cell adaptation, the dampening responses that result, how long we hold onto antibodies, all these things are impaired as we get older. So, no judgment required, but there is the reality of the matter and so, the experience with pediatrics, young adults, very different than what we see in our older individuals.

Dr. Blanca Gonzalez:

And even in our immunocompromised patients, I think the ones who tend to be sicker are the ones who are in more direct contact with the virus is lung transplants, or those whose net state of immunosuppression is extremely high, such as large multivisceral transplants. Those are the two groups and, of course, our bone marrow transplants at a certain point. But still, children, their outcomes in even immunocompromised are much better when you compare them to adults because a lot of children have seen the virus before.

Dr. Steven Gordon:

Well, I truly want to thank both, Dr. Gonzalez and Dr. Koval for being here. And before we pivot, I want to throw out something else. Anything that you would suggest for the audience maybe to read, could be medical, not medical, if it's on your nightstand now, or something that you might recommend?

Dr. Christine Koval:

In general, or about RSV?

Dr. Steven Gordon:

Yeah, in general.

Dr. Blanca Gonzalez:

I mean, what am I reading now? I'm reading Chekhov, so nobody wants to read Chekhov.

Dr. Christine Koval:

Well, I've been reading biographies of our founding fathers, and I think these are instructive lessons for our current day in that we have always had a messy country and messy political system, and it hasn't changed. Nothing's changed. There's been a lot of vitriol and a lot of people not liking each other, but we've made it work for over 200 years and hopefully we will continue.

Dr. Blanca Gonzalez:

I've been reading a lot of fiction a lot of Latin American fiction so the political elements are always there, how governments destabilize regions and it's the population that pays for it.

Dr. Steven Gordon:

Well, thank you both. Again, my name is Steve Gordon, Chairman of the Department of Infectious Disease, and this has been another series in the podcast focused on RSV vaccines. Thank you two both so much.

Dr. Raed Dweik:

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.