Infections after Transplant

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Tuesday, April 20, 2021

Presenter: Janice (Wes) Brown MD, Professor of Medicine, Stanford Health Care

Presentation is 37 minutes long with 21 minutes Q & A.

Summary:  Bone marrow, stem cell and cord blood transplant recipients have an increased risk of infection until their immune system has fully recovered, which can take many months. This presentation reviews the types of infections transplant recipients often acquire and ways to prevent and treat them..

Highlights:

• Although there has been progress in reducing transplant mortality, late infections still account for roughly 11% of premature deaths after transplant.

• Rebuilding the immune system is a complex process that takes time, so infections as late as a year after transplant not unusual. Having normal blood counts does not necessarily mean a transplant recipient has regained full immunity.

• COVID-19 mortality among transplant recipients is higher than among the general population, but has been declining recently. Early aggressive treatment with monoclonal antibodies and remdesiver has shown promise in these patients. Vaccination against COVID-19 will also be helpful, even if the immune response is not as robust as in the general population.

Key Points:

(03:42) Pulmonary disease and graft-versus-host disease have the biggest impact on irisk for infection after transplant.

(04:58) The risk of transplant-related infection declines over time, although the aging process itself is associated with a greater risk for infection.

(06:48) Infections will happen; the key is how well does your immune system resolve them.

(09:47) Infections are less a setback than a learning opportunity for your immune system.

(11:42): Graft-versus-host disease weakens the immune system.

(14:01) Immature immune systems can under- and over-react to pathogens.

15:26) Reducing exposure to sources of fungal infections is especially important for immunocompromised people.

(19:53) Some foods can pose infection risks. Unpasteurized and imported foods may be especially risky.

(21:48) Travel can expose us to unaccustomed sources of infection, and your care team should be informed about such travel when diagnosing unusual infections.

(23:58) Pets can pose of risk of rare, but potentially life-threatening infections. Simple precautions can reduce these risks and people should seek treatment at the earliest signs of infection.

Transcript of Presentation:

Note: In this presentation the speaker(s) sometimes uses the terms “BMT” or” bone marrow transplant”. For purposes of this presentation, both of those terms also apply to patients who have been through a stem cell transplant.

(00:01) [Lynne Spina]     Introduction. Hello. My name is Lynne Spina, and I am your moderator. Welcome to the workshop: Infections After Transplant. It is my pleasure to introduce Dr. Wes Brown. Dr. Brown is the Chief of Infectious Disease and a professor in the Divisions of Blood and Marrow Transplantation and Infectious Diseases at Stanford University Medical School. Her interests include immunodeficiency and how to enhance and/or rebuild the body's protective immunity. Dr. Brown is a leader in the design and execution of clinical trials of new treatments for infections that have significantly improved the outcomes for high risk patients. Please join me in welcoming Dr. Brown.

(01:00) [Wes Brown]     There has been progress in reducing transplant mortality. Thank you so much. I would like to thank the organizers for this opportunity to meet with you because I've considered every day of the past 30 years working with transplant patients and their families as one of the true privileges of my career. During this time, we've made explosive advances in the treatments and diagnosis of infections and these advances have been truly unparalleled. They have resulted in not only slashing the mortality rate in the first year following transplant, and then, I think this is important for our patients to know: these improvements could not have occurred without the bone marrow transplant patients and population. And they've had broad reaching effects on a number of areas of transplantation and medicine from cancer patients, to solid organ transplant patients, to rheumatologic diseases, trauma, and now even COVID. These advances absolutely would not have been possible had it not been for the brave hearted spirit of you and your family and your support team, and all that you have gone through. I can state this categorically as not an exaggeration and the transformation of our medical field has been nothing short of miraculous.

(02:19) Many of the guidelines and questions you may have, especially if you're at the stage where you're facing transplant in the early part, can be found in well written guidelines, many of which will been updated and you can find online. Certainly if you have difficulty, I'm sure the team at BMT InfoNet can help you.

(02:39) Late infections  account for 11% of premature deaths after transplant. It's a little too comprehensive to go over today, so what I'd like to focus on is the period of infections that occur after the first year. These are generally referred to as late infections. Two large studies, again also these can also be found online, come from the City of Hope and Minnesota. and also another large, consortium group, which found that late infections in the absence of graft-versus-host disease accounted for 11% of premature deaths. Again emphasizing the need for recognizing and treating the infections effectively and aggressively in this population that it is at risk for prolonged periods of immune suppression.

(03:25) Now, when we start there with that statement thinking, "I've made it through transplant, now you're telling me this?" It can be discouraging. But I hope today when I go over some of the procedures that might help determine risk and also what to do to maybe reduce those risks.

(03:42) There are many risk factors for developing transplant related infections. So, what does determine the risks? Well throughout the transplant period, there are a number of factors that are really out of your control, unfortunately, that determine your risk for infection. Some of these are more important during the early post-transplant such as underlying disease, the type of transplant, preparative regimen, the source of your graft: is it umbilical cord, an HLA-match, HLA-mismatch, T-cell depleted; how related the donor is to you. Is it your own cells or someone else's cells? All these things, as well as conditions you may have prior to transplant, impact your risk for infection. And these have been well-studied and there are a lot of procedures put in place to mitigate risk and to diagnose infection early.

(04:31) Pulmonary disease and graft-versus-host-disease have the biggest impact on infection risk. However even after transplant, the first three months or one year, the time since transplant, starting from day zero all the way through, matters, in a good way. The further out you are, the more your immune system has had a chance to rebuild itself. Along the way, or pre-existing, if you develop pulmonary disease and graft-versus-host disease, these two features probably have the biggest impact on your risk for infection.

(04:58) The risk of infection declines over time after transplant.  So, what are we talking about here? Another large study of 10,000 patients was published in JCO about 10 years and being really looked at, but holding up, is it declines over time. So, the blue bars are the percentage with infections and during the first two to four years, five to nine years, or 10 years are the gray bar. And they broke it down based on disease, trying to understand if there was a difference. The two main outliers are MDS and Aplastic [anemia] where it seemed like after 10 years there was another risk for infection wave.

(05:37) There's two points I want to make here. First of all, in all the other diseases, you can see it reduces to less than five percent risk for late death after transplant due to infection. And there may be something about these two diseases, themselves, not any particular failure of transplant, but maybe need for treatment or other issues that causes this apparent bump.

(06:03) Having said that, these are small numbers of patients. So basically the take home point is there is an ongoing risk, but there are out of 10,000 patients, the numbers are small. And one other thing they mentioned that's not represented here is, of course, during this time, we get older and being elderly, whether it's the beginning or the end, is a greater risk for infection. This is true whether you have a transplant or not.

(06:29) So, my topics for discussion that I'd like to focus on are a couple questions that I get asked a lot. First of all, "My counts are normal. Do I still have to worry?"

(06:39) Secondly, the specific risks that are commonly encountered in daily life. "How do I deal with those and what can I do to reduce the risk?"

(06:48) Infections will happen; the key is how well does your immune system resolve it. So a few basic principles, it is trite to say, but it's hard to remember for many people the life before transplant, how you didn't even really have to think about infections mostly. I should say life before whatever disease brought you the transplant. But it's an important part of life and in fact, it's an important issue of how your immune system is going to evolve. So, it's not always bad. The most important issue is how your immune system resolves the infection. Not that you got an infection just like rest of us, but how does it resolve it? And outcome is always going to be better with early diagnosis. I'll return to that later and how you can help make sure your care system is going to assist you in early diagnosis.

(07:40) Reconstitution of the immune system is not a linear process. I can tell you that the reconstitution of the immune system is frequently not a linear process. And so, what may appear to be setbacks are not necessarily a harbinger of any failure of the transplant. It's simply like all things in life: you may have good years, not so good months, and then improve from there. And it definitely may take some time for you, yourself, and your doctors to learn how your immune system is evolving.

(08:09) Immunity involves a complex mix of interacting cells. I put this slide up not... I mean, it's beautiful in many ways and it's from that guidelines paper I mentioned before, not so much to either scare you or overwhelm you with all the details, but to illustrate how the immune system, reading left to right, rebuilds itself. As you may see from the top, the cells have to go from the neutropenic period which we all count as our cells coming back, and then it still needs to develop both cellular immunity which is another set of cells, mostly lymphocytes and NK Cells, and then finally B cells and CD4 cells at the end. That's just the beginning in terms of numbers. They now have to learn how to interact with each other effectively and I will get to that.

(08:54) Rebuilding the immune system takes time, so lingering infections a year out are not unusual. But what I want you to focus on is, if you look at different groups of organisms, bacterial, the teal; viral in blue, and fungal, you notice that there is, and this is fascinating for us who study to try to understand the immune system and how the organisms behave, but you'll notice that over time, they're not a consistent risk. And even though, yes, at day 365 you are still at risk for these infections, in the absence of graft-versus-host disease, this risk will continue to decline substantially. So the message is, rebuilding a competent immune system to all classes of organisms does take time. So if by year out you're still having some infections, that again is what largely would be expected.

(09:47) Effective immunity involves cells, timing, and precision in the response to infection. So we talked about, "My counts are normal". Again, another complex slide to tell you, it's not just the pieces being present but they all have to interact in incredibly elegant and complex ways. But the general message is, there are three main ways that our immune system has to work. Now most of think, "Oh, I've had a transplant or cancer. My immune system is weak." Well, that's only part of it. Actually, towards that end, the immune system needs to know when to turn on, assuming there's appropriate cells to turn on, and then it has to have a precision. You don't want it reacting to your own skin cells, something like graft-versus-host disease, and if it doesn't know how to turn off, then all of us on this planet would be dead from the first cold we had. And this is what we're seeing from COVID: the inaccurate turning off of inflammatory response.

(10:44) Infections are less setbacks than learning opportunities for your immune system. So if you look at the elegance of this, it does take time for the immune system to get it right. Many branches of the immune system are needed to develop this in order to really be functional. Again, I'll mention again, it's not a linear process. It always breaks my heart to see the disappointment on someone's face that they have to come in and the fear that they don't want to articulate that things haven't gone well. But that's really not the truth. It really, as you probably have experienced or will experience, we tend to hospitalize and treat early to protect and then analyze later. But almost always, this is a learning opportunity for your immune system rather than a setback.

(11:30) There are organisms that are tissue-specific and pathogen-specific that will and may take extra time and you may be at risk for and I'll touch upon some of those.

(11:42): Graft-versus-host disease itself weakens the immune system. Now in the next slide, I think this deserves very special attention. For anybody in the room with graft-versus-host disease or has heard of this, this is something that all of the slides will still pertain to you, but the tenor of what risk you may be at is different. And it's not worthwhile to sugar coat it for you; it does require more diligence and working closely with your doctors because graft-versus-host disease itself, when the graft you have doesn't fully recognize parts of your body, other systems of your body, as part of its new home, it belongs here together. And it itself causes impairment of immune function.

Wes Brown (12:33) :I'll say that again: graft-versus-host disease itself weakens your immune function. That's why if you have it, your doctor or your care team, I shouldn't just assume who works with you, your care team may not say, "Oh. Stop all immune suppression because it's going to increase risk of infection." In fact, you have to control the graft-versus-host disease in order to reduce infection. So, you actually need the immune suppressants. At that time, many prophylactics, meaning trying to prevent infection, antibiotics will be given to you. This is a practice that we try not to do in other areas of infectious disease, but in this, it's important.

(13:16) Overall health maintenance is important in regaining immunity. Health maintenance: it becomes incredibly important. Trying to keep your other organs healthy and when I say health maintenance, I mean physical activity all the way to your dentist and vigilance because your immune system may not report things the way that it would in the absence of this. And the antimicrobial therapy I'm talking about may be continued for the duration of the immune suppressive therapy and/or longer at times. And you are at risk for infections from various organisms and various classes of organisms. So not to scare you, but I think that it's important that people with graft-versus-host disease have a very close working system with their physician.

(14:01) Immature immune systems can under- and over-react to pathogens. Now when I write this, and I talk about the immune system, even when it does react, and I think for myself, very personally, I didn't understand this until I became a mother watching what happens. And that is, the evolution of the functional immune system is that first, it's too young to interpret and respond. So, it may let things go. And then, anybody who has seen a child, have a child or a teenager or a tantrum-aged person, including a teenager or a less than mature adult have seen an over exuberant response to something. It's counterproductive. And the most challenging thing is, you don't even know sometimes what it is that they're upset about. So for example, your immune system could seem like it's going haywire and the doctor can't find, the team can't find the specific trigger. Is it your graft-versus-host disease or is it an infection? So, that's a kind of state of the art. That's why we often just treat very broadly.

(15:03) And then after the tantrum, frequently, you have this acquiescence when the immune system hasn't really helped and really doesn't even know what it's responding to. So, that's something we face and you can see elements if you read detailed cases of even COVID now. So, this is part of the immune system.

(15:26) Avoiding exposure to sources of fungal infections is important. So, I want to focus now again on everyday life. What are the things that you need to do or be aware of? And I would say be aware of more things to do, or don't need to do. So I have this slide here, what do these activities have in common? This is marijuana, this is moss. This is construction, which I happen to be in California... moving the lawn, which I think is hilarious. It's bad for your health. As a kid when I had to mow the lawn, I kind of agreed with that. And then, this is actually herbal medications, fresh herbal medications. What do they have? They pose a risk for invasive fungal infections and other soil organisms. And this is a word you may want to remember, but it's because it's not the typical fungal, it's a bacteria.

(16:17) What do I mean? Do I mean just avoid all of these? No. But there are ways to mitigate. For example, instead of smoking or ingesting marijuana, even ingesting, the spores of marijuana and all plant material can survive the acids of the stomach. It can survive burning, even in the cigarette or any other kind of inhalation process. So, the essential oils are what we recommend people use safely. Should you avoid construction sites? Most likely, but if need be, if your job puts you there and you may want to consult with your physician as to whether wearing a HEPA filter mask when there's a high exposure is appropriate to do, same with mowing the lawn or gardening. This is not forever, but I think again it would be good to have a dialogue.

Wes Brown (17:08): There's also unbelievable medical benefit which most Western practitioners and myself included do not understand about herbal medications. I am an Infectious Disease Specialist, so we do know that there are risks of fungal infections being carried in the spores themselves. So again, I would be quite careful again, and I assume they have active ingredients. I do. Now the challenge is, are they going to interact with your Western medications? So, it is worth having a dialogue with your practitioners.

(17:42) Inhalation of fungal spores can cause multiple infections in immunocompromised people. But inhalation of fungal spores is the most common. These are some examples of beautiful fungi. I put the map back here because there are fungi that are unique to different areas of the country and the world. So, you do need to have that dialogue, and you may have been exposed to it, no knowledge whatsoever. You didn't have to be digging. We simply breathe these in, and they inundate out. But that wasn't a cause for alarm because when your immune system reconstitutes itself, you will be able to protect yourself from it. But because inhalation can lead to brain, sinus, oral and gastrointestinal infections, if you have any symptoms referable to those you can't explain and especially sinus, definitely have those investigated. And especially if you've not had a history of sinus infections before.

(18:31) So, why do I put this? I call this my Costco slide. I don't know if I'm the only one who's ever gone and seen these beautiful peaches, bought too many and then never quite get around to them. I put this up because normally, you were just walking around. Normally, that's how we inhale other things. We're digging, so we know. But don't have people smell this and say, "Do these smell good to you?" My advice.

(18:54) Minimizing exposure to dust and wearing masks can reduce infection risk. But you can reduce them, as I mentioned. Avoid disrupting anything that will result in aerosolization. In other words, don't tear out walls or other structures. It'll create dust. You can have them done. It's probably best if you yourself don't do them. And just move out if necessary or just wait until it settles, the dust settles. And simply wetting the dust helps. And you can wear a mask depending on what's appropriate. We have our patients wear this HEPA filter mask. Rarely do you need an N95, but these are probably useful if you are working with chemicals or other fine particulate matter. And we all are familiar now with the standard masks. This does not protect you per se against anything but, as we've talked about, likely spread from respiratory viruses to a certain extent.

(19:53) Some foods can also pose infection risks. What about food? There are a few organisms, especially some vibrio, especially if you're in Louisiana or the Southern coast of the United States, but mostly raw foods, this is true for any of us, do carry potential for organisms. Now, that doesn't mean you have to avoid them completely. This is your life and you should enjoy what you enjoy. And I just would keep mindful of it. So if you develop a symptom, especially after eating or other, just keep your care team aware of something if you develop a symptom. If they're not your favorite food, then it's just probably best to stick with well- cooked food.

(20:39) Unpasteurized foods can be a different story, especially if they're imported. We all are aware of the listeria E coli outbreak that came from Iguala. Well maybe not all of us, I'm much older, but that was actually a fairly lethal outbreak. So if you can, and now even imported cheeses are mostly pasteurized, but this can be a serious issue. So, check amongst the types that you like and see if you can find that it's pasteurized. For all of us, just check for alerts of food-related outbreaks. Cantaloupe recently here, lettuce at times, there's nothing special that you need to watch out for. I would just wash your fruits and vegetables as you normally would. You don't need to buy any special machine or procedures. Berries can be challenging, but I would not advocate avoiding them if you're past a year out and don't have graft-versus-host disease. They just can be challenging to wash without really ruining them. And as I've stressed before, do not let someone stick your nose in the food and say, "Does this smell good to you? Do you think this is still good?"

(21:48) Travel can expose us to unaccustomed sources of infection. So then, much is beyond the scope because there are different organisms that you can be exposed to and even carry and that can come back later. So, share the history of your residences and travels with your care provider so that if they need to, they can evaluate for certain things such as parasites, tuberculosis or endemic infections, meaning infections that are in the soil but different countries have different infections.

(22:18) We all in this country, or everywhere, have the bias of what we know. For example, I always tell people, "Here in this country, we may not be as fast at diagnosing tuberculosis as they would be. They can whip fast in countries where it's very common like India and China. And so just to keep that in mind. If you have traveled to interesting places, don't assume that we are as up to speed with understanding that. We're just making them aware that, you've been there and that will help."

(22:55) Now, perhaps the most important part of our treatment are pets and other members of the family. I get a lot questions about this. This is my puppy. We don't need to be told the healing benefits of pets and family members, although family members can be a little bit more complicated sometimes, but the healing benefits of pets. This has been studied. Critical to healing is increased activity and pets can offer you that. People have studied in healthy people even, the reduction in cholesterol and triglycerides, the decrease in cardiovascular events. Critical to our patients is a decrease in depression and mental stress and absolutely higher self-esteem, especially. Your body has gone through a lot of different changes since transplant and cancer treatments, so these are not minor benefits, and few that any of your healthcare providers can provide to you. So, only family and pets can probably help with this.

(23:58) Pets can pose rare but potentially life-threatening infections. But they can carry infection. Before we go on, I want to say that these are not common. These are rare infections and the only reason I bring them up is because they unfortunately can be life-threatening. So, it's worth knowing, if you develop a syndrome, but it is not worth being afraid or not interacting with your pets with some exceptions.

(24:20) Cat owners should take precautions to avoid toxoplasmosis in litter boxes and gardens. So with cats and kittens, their scratch and sneeze can bring infection. They can have bite-related infection, that's something more than you would want to know, mostly the bites and the scratches. And this is the one that I've heard and I have yet to meet a person who is sad about this, but really transplant patients I believe should not be emptying the litter box. Because in stool, you'll find toxoplasmosis, which is a parasite. It can be difficult to diagnose and can cause a wide range of infections, especially brain abscesses in our patients.

(25:00) Now, does this mean you can't garden? No. But you should know that there are a lot of feral cats and they use your garden as a litter box. So, you have to assess your garden, how accessible is it, do you find evidence of that and we can maybe talk either now or offline about what are the mitigations you can use. But gardening is very therapeutic as well if you like it. I happen to be terrible at it, but if you're good at it, it's therapeutic. And I think it's very valuable to be able to just take stock of what's going on and modify your indoor garden if necessary.

(25:39) Seek treatment at the earliest signs of infection. Now, what about these? Why am I telling you this lovely life cycle? Because I just want to remind you that it's not the cat per se, but it can be the insects that bite them and then you can pick it up from the cat. So there's nothing wrong with the cat per se, but if they go outside, they're exposed to more of these risks. What you want to look for in these things, if you get swelling or cellulitis at the site of a wound or your joints start to hurt, even if they're not inflamed, and remember, you may not have as much inflammation, please go and see your doctor. It can be simple as a bacterial infection, a local bacterial infection and if not, they may just want to monitor it. But similarly, from a bite, you could get fever, fatigue, headache, poor appetite, swollen glands, especially in the head and neck. If you just get anything that's vaguely related to this, please let your physician know. The earlier you get treated, the better. And there are treatments.

(26:45) Toxoplasmosis, I had mentioned in the stool of the cats. If you do not touch the litter box, then you should be fine. You may already be positive for toxoplasmosis, which they may have determined following the transplant, and you can ask your care provider if they've done that. And I mentioned the cats in the garden. So, that's the question for you, for these other infections, it's perhaps better if your cat stays inside, it's an indoor cat. But then again, they could be pooping outdoors, so you'll have to know your own situation in terms of what risk you have. But for now, let your family members and forever, let them clean out the kitty litter. Again, I've not met anyone who's sad about that.

(27:34) Dogs can also pose risks to immunocompromised people. Well, dogs too. This is my dog when he was a puppy. He can transmit infections. These you've heard about or may have lately because of the dramatic complications that can occur from a bite or actually... well, we'll stick with the bite. There is this organism, capnocytophaga. You can also get methcillin-resistant staph, aureus, or a mixed bacteria. So, dog bites are serious. And even if they aren't inflamed, you should go to your doctor, even if it's your dog that you've lived with forever because these are natural organisms in their mouth. They don't have to pick them up from anyone. It's a common pathogen. Cats can also have those, which is why you... when a cat or dog fight and they end up with intravenous medications. But it's treatable.

(28:23) Now from the stool, they can get a variety of things: salmonella, campylobacter, and giardia. Picking it up through the plastic bag is perfectly fine and then the typical hand washing. But the saliva, if you get saliva through a bite, scrub the wound or go to the Emergency Room especially after a bite. You may end up on intravenous antibiotics. But remember, these are rare. They're rare with healthy people; they're rare with immunocompromised patients, but they can be life threatening and fast moving. So, don't be shy about going in.

(28:59) I put this because it's turned out that in addition to giardia, campylobacter and salmonella, dogs may transmit norovirus. Norovirus is something which is self-limited in healthy people but can be a very big protracted problem in immunocompromised patients, especially if your immunoglobulins are low. So if you have persistent diarrhea, you don't have to throw the dog out, there is no treatment, but I think that that's something to check with your physician about. Sometimes there's no direct treatment, but they're can be supportive treatment.

(29:37) Birds can also pose risks. I'm finding that most people don't have birds. Birds, I had one patient who was so energetic, went back to his farm right after transplant, cleared out his chicken coop and got psittacosis and ended up in the Intensive Care Unit. It's important because you want to have others designated to clean the coops, make sure the cages are cleaned outside and don't kiss the birds. And there was an outbreak in New York City about parrots. It was a little bit humorous, but for our patients, it can be something serious.

(30:10) COVID poses risks but also has normalized mask wearing and other precautions. Now, I will take this because other human beings don't spread too much to us that we really need to worry about except, and I know you've had a great talk about COVID, so I'll only put a flyer out here to say there are many other viruses. The good news is we can prevent influenza by vaccination. And as you know from COVID, it can be airborne transmission by aerosolized or it can be contact transmission. So, the one thing that COVID maybe has been good for our patients is, my patients have told me it's normalized it. They're not the only ones having to wear a mask. They're not the only ones having to watch out for groups of people. And so, maybe I hope some people will have an understanding of what you go through. But you also know that it is highly effective to do the social distancing and please follow the patterns of influenza, that vaccination will be helpful even if your immune response isn't so robust.

(31:11) COVID may affect transplant recipients differently. I'm going to flip to this slide: our personal COVID protocol at Stanford. Actually, I should go through our data so far. We had about 90 patients. Sixty actually to 75% were household members of the source and median time to infection, this has now changed, it's over two years. Rituximab was a particular risk, whether you've had it recently, six months or even three years ago. And our patients have a longer course of shedding. That doesn't mean they're sick the whole time, but they can shed for, instead of the typical two weeks that you hear for healthy people, up to eight months is our longest so far. Our mortality is about 15%, which is higher than the national average, but it's been declining precipitously since we started instituting monoclonal antibody and Remdesivir.

(32:06) Aggressive early treatment of COVID in transplant recipients is advisable. So, our new protocol is to give monoclonal antibodies as soon as possible. We have a low threshold for giving Remdesivir, even if some of the patients are not hypoxemic, but especially if they have received Rituximab or an allogeneic patient, for example. We assess carefully secondary infections. We have a program where people text their oxygen saturation, fever and symptoms to one of us daily and then our plan is to vaccinate as early as 30 days for an allo and 60 days for all the others if there's no graft-versus-host disease. The platelet count is because it's an injection. So, we have been studying some other approaches.

(32:59) And if you have a chance, if you're at that period of time within a year, there's a very large, very important study going on sponsored by the CTN [Clinical Trials Network] and CIBMTR [Center for International Blood and Marrow Transplant Research] to look at immune response. So if you have not received your vaccination or even if you have, please reach out to your program to see if you can participate in this trial. It will tell us a lot more than just whether you need antibodies. It will help tell us, how do our patients manage to develop immune response?

(33:36) Managing health of skin, teeth, GI tract and sinus is important. So, I'll go through... I think I did have too many slides. I just want to go on to the highlights of certain things. You are at increased risk for bacterial infection, any of these issues that we've talked about, but you can get vaccinated and these will help. But the more important thing, I think, is managing your health of your skin, your teeth and your gastrointestinal tract and your sinus/pulmonary status.

(34:06) Oral, I cannot stress enough of going to your dentist regularly, especially with graft-versus-host disease because it can result in a dryness of the mouth which then leads to a profound compromise of your teeth leading to caries and tooth loss.

(34:24) Follow vaccine guidelines carefully for yourself and household members. . Also speaking of vaccinations, there's a whole vaccine guideline. Don't copy this down because it keeps changing to a certain extent. But basically, for some it's 12 months or 18 months post-transplant, we vaccinate you for all of those vaccines that you should have received as a child. These are important. It kind of resets the clock for you and it's hopefully helpful. Though to be honest with you, there have not been tremendous numbers of childhood illnesses. Perhaps the one thing now is that there's a new Varicella vaccine, Shingrix, which is being recommended for all patients.

(34:58) More important than that is vaccinating others in the household. That's true for COVID and it's true for every other vaccination.

(35:11) It’s important to consult with your health care team about any concerning issues. I know I'm going over my time, but I want to say a couple things. What can I do to reduce my risk of infection? I mentioned some of the issues with the vaccine. Take any prophylactic antibiotics you're prescribed. If you're not able to or have concerns, share that. But the most important slide I think is here: partner with your healthcare team. Even if you do not feel well, report your symptoms and share your concerns and seek help early. If you're diagnosed with an infection, work with your care providers and notify your transplant team. I look at you now as I put here, don't stop enjoying your life but treat your body as a Ferrari. Sometimes, the Ferrari mechanic is the only one you really want to go to, but a lot of times, your local doctor knows you better. So, you need to collaborate with your transplant team so if there are any other new tests or other things you're observing, and hand wash.

(36:08) So, I'm not sure I've left enough time for questions. But I want to say-

(36:16) [Lynne Spina]      No, you're good. Doctor, go ahead and wrap up. You're good.

(36:21) [Wes Brown]     ... Okay. Great. I just want to say, if you're ever out at Stanford, it does look like this. It's pretty beautiful and I hope you'll look me up, but I'll finish my talk there and I hope I left some time for questions.

(36:36) [Lynne Spina]     Q & A. Thank you, Dr. Brown for a very informative presentation. We do have many questions in the queue, so we'll start them now. And as a reminder, if you do have a question, please type it into the chat box on the lower left hand corner of your screen.

Question & Answer Period

(36:54)      So, our first question is, "What are the best practices to avoid getting an infection that jeopardizes the BMT? And I think most importantly of this question is, what are common mistakes?"

(37:13) [Wes Brown]      I'm going to answer this a little bit backwards. I think one thing I don't want people to be is fearful. I know that's easy to say because then, people aren't telling you, "Well, do X, Y, and Z." But probably the best practices are to keep yourself in as good of shape as you can, avoid inhalation or smoking or vaping, and anything that would expose you to spores. Other than that, by keeping in physical shape even through the transplant, even if it means just walking from your bed to your bathroom, I think that's probably the best thing, and recording any symptoms early. Don't be shy about if you just don't feel well but don't have a fever. I think those are the best. I know it sounds vague; it almost sounds trite, but I think those are the best because we'll be looking out and screening for everything else that you might be at risk for and try to mitigate that.

(38:07) [Lynne Spina]      The next question: "How do you measure the strength of your immune system?"

(38:13) [Wes Brown]     I would like to talk to this person because that will win the Nobel Prize. There really is none. And in fact, the reason I'm passionate about this field is I feel like the infections that we see, and if you remember that timeline, it had very precise windows of infection. I think that tells us where your immune system is at. There is no number at this time. We have a lot of laboratory tests, but none that we can directly correlate to infection. It's not like HIV where the CD4 count was basically all you needed to know. What they've done to your immune system is far more complicated, not to mention that before, you may have had a disease that may have affected your immune system or chemotherapy. So, it is the holy grail, but I also suspect it would be different for each kind of organism.

(39:10) [Lynne Spina]      Okay. "Some of the side effects for specific meds I am taking say they can cause UTIs. How does a medication actually cause an infection?"

(39:23) [Wes Brown]      You stumped me on that one. I have offered to the team that if there are specific questions they can forward to me, I'm happy to contact you separately and talk about it.

(39:38) [Lynne Spina]     All right. Well, we can handle it that way. No problem.

(39:40) [Wes Brown]      Okay, great. Yeah. I'm sorry. That stumped me.

(39:43) [Lynne Spina]      That's okay. "How long after transplant do you need to stay away from mowing lawn and actually gardening too? Three months, six months, a year?"

(39:57) [Wes Brown]      Yeah. That's a good question. Gardening creates less aerosol and if you're comfortable wearing... they have a filter mask. I don't think that there's a reason you have to stay away from it once you're off the immune suppression. Mowing is a more challenging issue because you're aerosolizing a lot. But again, if you're willing to wear a HEPA filter I think as soon as you're off immune suppressants and that should be fine. The HEPA filter mask really does make it easier and does protect you.

(40:29) [Lynne Spina]      And here's another practical question: are frozen berries in smoothies okay? About half frozen vegetables and fruits in general, "How about frozen veggies and fruits in general? I'm 60 days post autologous transplant for MCL."

(40:47) [Wes Brown]       Yes. I think that frozen berries are fine because they tend to be washed and flash frozen and same with frozen vegetables and fruits. And I would just speak with your nutritionist about how to maximize nutrition from them, or don't, and just enjoy them however you like them cooked.

(41:12) [Lynne Spina]      Okay. "What do you think of probiotics for regulating GI function? I'm nearly eight years out from transplant, have chronic GVHD, lungs most serious, but I am stable."

(41:26) [Wes Brown]      That is a very complicated question and one of extremely exciting study. Perhaps I'm the wrong person to ask partly because it's not my area of study. So, I will defer you to some of the other speakers. But I have to, just for my two cents worth of infection, I feel like the human body does best when we give it the normal... when we... the care providers... granted, you've been through a lot. We've modified a lot, but anything that can be returned to normal, normal food is the best way to repopulate your gut.

(42:03) [Lynne Spina]      Okay. Then next question is about COVID-19. Obviously ... It's on top of people's minds and this person has heard apparently that you shouldn't be getting it within less than one year of transplant. So his question is, "What and why are there issues in getting the COVID-19 vaccine in less than one year of transplant?" And I know you've done some studies. You probably can speak specifically to that.

(42:34) [Wes Brown]      Yes. I feel, and our largest societies is, both ASTCT - American Society for Transplant and Cellular Therapy and American Society of Hematology, both feel that we should approach the COVID vaccine the same way we do influenza vaccines. Why? Well, we know that our immune systems, patients' immune systems will not be as robust as they were before, or other people's, but even with that, there is some protection. You don't need 100% to generate 100% of the same antibodies. Plus, it may not be only the antibody response.

(43:12) Therefore, the recommendation of these groups is not to wait that long, a year after transplant. First of all, the whole benefit is to try to protect you now. But I think that hopefully the people taking care of you, the dialogue will change and they'll understand that some of the dialogue was colored by the shortage of vaccines. Now, the vaccines should be available to all and there is no toxicity that's being seen in the bone marrow transplant patients or any patients, Johnson & Johnson discussion, aside, right at this moment being reviewed.

(43:46) And here's my other point: if you want to participate in the trial, that's a good way, even if your care providers aren't comfortable giving it to you, or not giving it to you, not making it accessible right now. There are ways you could participate. And we will be studying, let's say that our patients do not make a great antibody response, that doesn't mean they're not protected against COVID, at least death from COVID. And then knowing that, we might lose people later. So basically, our bias is to get the vaccine. We'll be monitoring, you or your doctors can monitor you, and then if at times, there's a booster, we can figure that out as science progresses.

(44:35) [Lynne Spina]      Okay. Thank you. The next question touches upon your point about oral care. "Has avoided the dentist because of COVID issues. Is it better to go if the doctor reassures me that they are following COVID restrictions?"

(44:54) [Wes Brown]      Yes, there are. And there have been, I think it would be reportable how many transmissions from a dentist to a patient. They have taken such great care or practices. So, I definitely think it's important to go to the dentist, for everybody to go to the dentist on a regular basis. When you're in the throes of your platelets being low or on immune suppression, your team will tell you whether it is or is not safe, but it's an area we infectious disease people know we overlook and it is a huge source of lots of bacteria that do end up causing serious problems.

(45:38) [Lynne Spina]     "Is TRALI considered an infection or just an injury?" Transfusion-related acute lung injury is what this person is relating the question to.

(45:49) [Wes Brown]      Yes. People thought that there might be an infectious to trigger it, but looking at all... and there may be things that look like TRALI that have confused the picture, but TRALI in its definition, especially related transfusion, is an injury, a lung injury. I'm not just exactly sure whether it's an antibody or a cell median injury, but it is an immune response.

(46:10) [Lynne Spina]      Okay. "Are there special considerations for patients with B cell neoplasms, even if they have undergone an autologous transplant?"

(46:26) [Wes Brown]      For patients, yes. Interestingly, especially if you, in this era of COVID and vaccines, if you receive Rituximab, it's becoming clear that that may have an impact on how your body responds to what we call novel antigens, like COVID. Or, how you're going to respond to a vaccine. It may not be as robust. So, those are the things that I think I would keep an eye out for you or whosever received a treatment.

(46:59) [Lynne Spina]      Mm-hmm (affirmative). "If I wear surgical plastic gloves to clean the cat litter and then immediately dispose of them and disinfect my hands, is it safe enough to avoid toxoplasmosis?"

(47:15) [Wes Brown]      It is, but don't tell your husband or wife that. I'm just kidding. It is. Try not to aerosolize, it can be hard.

(47:30) [Lynne Spina]      "How long should BMT patients avoid changing poopy diapers?"

(47:34) [Wes Brown]      Oh, I don't think there's anything wrong with changing poopy diapers, really. And I think that just hand washing is important, right? And assuming your child isn't ill or have something like norovirus or rotavirus, but if you're child's not ill, I think it's actually a lovely bonding experience to a certain extent. But it is also something you could ask your spouse to do.

(48:02) [Lynne Spina]      "Can GVHD affect the autonomic nervous system and cause symptoms that mimic symptoms found in long haul COVID caused by the immune system not shutting off?"

(48:15) [Wes Brown]     Yes. Absolutely. And that's an extremely good question. When we first heard about COVID, that's exactly what it made me think of, not just GVHD, but how an aberrant immune response acted. And so, yes. I think you have the same [inaudible]. It may not be the exact same cytokines, but it probably is the same process.

(48:44) [Lynne Spina]      "Can you comment on the risk of infections from sex?"

(48:49) [Wes Brown]      Yes. That's a good question. The main thing, and I skipped a couple slides, but graft-versus-host disease can affect the sexual organs. And it usually more manifests... in men, it can be complicated, but in women, it often manifests as dryness. And the only reason I bring that up is, anything that causes friction and irritation, whether it's on your arm or on your vaginal folds, it can put you at increased risk. And people who have a tendency to have urinary tract infections, that may still be there. That's a separate mechanism that exists in normal, healthy people. So you may face the same kinds, it may just be exaggerated. And I assume you're not talking about sexually transmitted disease per se. Those will prove true for everybody.

(49:43) But other than that, standard... now, sex is defined in so many ways. I have seen patients who have had an infection from oral sex; however, this is a minority of times. And I mean, that's vanishingly low minority of times. And I often worry that maybe I haven't seen as many sexual-related infections because getting back to a normal sex life is a difficult thing after transplant. So, I personally would encourage people not to be afraid to really... if lubricants are necessary and helpful, yes. If there's something like an overt herpes outbreak, use appropriate barrier mechanisms. And again, don't let it add one more thing that prevents you from enjoying that aspect of your life. People sometimes ask me about anal sex. Anal sex is more traumatic, but I can't for sure say that there's any increased risk as a result of it. I don't know if that answers your question. It's a very important question.

(51:02) [Lynne Spina]      Well, thank you very much. "I've been told to stay away from my grandson that received MMR and chicken pox vaccines. Can we meet outside over six feet and masked?"

(51:16) [Wes Brown]      You can and also, people have decided that it's likely is not highly transmissible. And if it is, we're talking about a week. So even though, in theory, it may be, most of the studies show that the children do not, even though it's a live virus, for those people asking, the MMR has live virus in it. And so, can it be transmitted? That's also even presupposing that you've completely lost your immunity to these organisms, which you may not have. So my answer is, yes, if you're just fearful or you're concerned, I would not... Again, it has to go through your comfort level. If you're worried, just a week away is perfectly fine.

(52:06): [Lynne Spina]  Okay. "Are urinary tract infections something to worry about?"

(52:12) [Wes Brown]      People who are prone to urinary tract infections will again find themselves at times, because... women, it may be a structural issue that predisposes a lot of women to urinary tract infections. So, yes. If you're getting them, definitely attend to those and report it to your care team. For men, men should not be having urinary tract infections. So any urinary tract infection in a man, with or without transplant, warrants evaluation. And then, there are other kinds of cystitis, which is an inflammation, it is not a specific bacterial infection like we're talking about, and those are different complications in transplant. I'm not sure if you're talking about that, but definitely, you need to get care for that whether you're a man or a woman.

(53:12) [Lynne Spina]      All right. The next question is, this man likes to fish. "Does fishing pose an infection risk?"

(53:20) [Wes Brown]      No it doesn't, as long as you don't get stuck or drink the water. There's no specific risk. It's just the hand trauma, fishing.

(53:31) [Lynne Spina]      Okay. "I am a long term survivor of 30 years with GVHD. How at risk am I at this point more than the greater population?"

(53:43) [Wes Brown]      Wow. First of all, congratulations. That's a difficult question. Everyone is so different that I think it would be a good question to ask your provider. I don't mean to skirt the question, it's just that 30 years is, that's on your side. That's really on your side that your immune system has to... may not be precise, but it's functioning quite well. So, I would ask your care provider.

(54:12) [Lynne Spina]      Okay. "Prior to transplant, my sinuses drained a lot, especially during exercise. After transplant, my sinuses seemed to drain all the time. Is this a potential sign of infection and should I expect to recover to pre-transplant drainage?"

(54:32) [Wes Brown]      If it's clear drainage, it's typically not a sign of infection. If you're having sinus pain or different quality, I would definitely ask your ear, nose and throat doctor or have them evaluate. I can't say from afar, but it doesn't have to represent an infection at all. Much of the drainage and the reactivity has to do with response to... for lack of a better word, I'll say allergens or environment signals. So, remember that your immune system, now, if you've had an allogeneic transplant, is now that of somebody else's. And for all you know, that person had a lot of seasonal allergies. So, I think that if you... you want to get a characterization of whether it's an infection, definitely bring this to your ear, nose and throat doctor for them to evaluate. He might be able to give you treatments too to reduce the drainage.

(55:36) [Lynne Spina]      "Can you discuss EBV prevention and management for patients who are more than a year post-transplant?" And please explain EBV.

(55:44) [Wes Brown]      Yes. EBV is Epstein-Barr virus. It's more known as the mononucleosis virus and it's a sister of cytomegalovirus and the herpes viruses. And like them, it is ubiquitous. The vast majority of adults already have had it without knowing they ever had mono and we carry these viruses in our bodies for a lifetime. So, there's no eliminating them.

(56:10) What they can do, especially if you have a T cell depleted graft, is it can reactivate. And sometimes it's associated with triggering something called post-transplant lymphoproliferative disorder. We don't see that that much in our patients late. So if it's late, another thing it can be is a marker of specific types of lymphoma. So if that also is what people have and they detect that, that may or may not be an indication for evaluation to see if the lymphoma cells have come back.

 (56:47) Having said that, if you get EBV acutely when you are transplanted, you're living life to the fullest, now you're back to the teenage years and you've got the kissing disease, it's not so bad, I guess. But people will discuss. A transplant infectious disease person like myself would probably give you antiviral where a lot of other people would not. I don't have a lot of data that it's going to make a difference or shorten the course, but I think that it's something I would consider.

(57:18) Which brings me again to one last thing I should have mentioned: there are a lot of us in this specialty field over the past few years, we call ourselves immunocompromised hosts or transplant infectious disease doctors. We often do things the exact opposite of our colleagues because you, the patients are almost the exact opposite of a healthy person will respond.

(57:42) But don't be shy. If you do get an infection or you do have a question, feel free to advocate for yourself. You will need both to work with your local team, but please use any resources you can find to talk to your transplant team, get a second opinion. I advocate for that all the time. Sometimes people aren't comfortable, but I feel like any doctor worth their salt, any care team will be happy to work with other care providers. But I do hope you'll advocate for yourself.

(58:17) [Lynne Spina]     Closing.  I think that's a good message to end on. We are out of time at this point. I would like to thank, on behalf of BMT InfoNet, our partners and thank you Dr. Brown for your very helpful remarks. We had a lot of questions today. There's so much interest in infections, obviously and we would like to thank the audience for all these excellent questions.