Managing Infections after Transplant and CAR T-cell Therapy

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Managing Infections after Transplant and CAR T-cell Therapy

Friday, May 3, 2024

Presenter: Erik Dubberke MD, MSPH, Professor of Medicine, Co-Founder of the Transplant Infectious Disease Service, Washington University School of Medicine

Presentation is 41 minutes long with 17 minutes of Q & A

Summary: People who undergo a stem cell transplant or CAR T-cell therapy have an increased risk of infection after treatment. This presentation discusses who’s at risk, when infections typically arise, steps taken by transplant teams to avoid and treat infections and steps patients can take to reduce their risk of developing a serious infection.

Highlights:

• Transplant and CAR T-cell recipients are at risk for "opportunistic infections" after treatment - infections that don't normally occur in people with a healthy immune system.
• People who had a transplant using donor cells (allogeneic transplant) have a higher risk of developing an infection after treatment than those who had CAR T-cell therapy or a transplant using their own stem cells (autologous transplant)
• Lifestyle choices, like practicing food safety and keeping current on vaccinations, can significantly reduce the risk of infection after transplant and CAR T-cell therapy

Key Points:

(02:38): People whose immune system is not working properly are prone to developing opportunistic infections – bacterial, viral and fungal infections that people with normal immune systems typically don’t get.

(05:05): Prior to transplant or CAR T-cell therapy, patients should be screened for past infections such as cytomegalovirus (CMV), varicella zoster virus (the virus that causes chicken pox) HIV, hepatitis B and hepatitis C. These viruses may already be in the body and can become activated in patients whose immune system is weak after transplant.

(14:00): Damage to skin and mucus membranes in the mouth or gut increases the risk of infection. 

(15:58): After transplant and CAR T-cell therapy, there are fairly predictable periods of infection risk based on the parts of our immune system that are being impacted by the transplant on CAR T-cell therapy.

(16:12): Until the stem cells engraft after transplant, ulcers in the mouth and intestines, and infections around the venous catheter are common.

(17:48): After engraftment, people transplanted with their own cells usually do not require ongoing medication to prevent infection. Those transplanted with donor cells, however, are still at risk of developing opportunistic infections such as cytomegalovirus (CMV), varicella zoster virus (VZV), and adenovirus, as well as infections caused by pneumocystis, toxoplasmosis and mold.

(19:46): Infections are fairly common during the 100 days after transplant, after which the risk declines, except for those with significant GVHD.

(26:55): Following four steps for food safety can help prevent infection: 

(31:31): For the first year after transplant, avoiding new pets is advised. 

(33:04): Additional precautions include wearing gloves and thorough handwashing after digging in dirt; avoid construction and remodeling projects, avoid crowds and people who may be infected.

Transcript of Presentation:

(00:01): [Jordan Sexton]:  Introduction. Good morning and good afternoon, and welcome to the workshop, Managing Infections after Transplant and CAR T-cell Therapy. My name is Jordan Sexton, and I'll be your moderator for this workshop.

(00:12): And it's my pleasure to introduce our speaker, Dr. Erik Dubberke. Dr. Dubberke is a Professor of Medicine in the Division of Infectious Diseases at Washington University School of Medicine in St. Louis, Missouri. He co-founded the Transplant Infectious Diseases Consult Service at Washington University when he joined the faculty in 2005 and currently serves as its clinical director.

(00:34): Dr. Dubberke has a long history of developing and reviewing pre- and post-hematopoietic cell transplant and CAR T-cell or CAR T therapy, infection prevention and treatment protocols. He's studying ways to safely target antibiotics to bacteria that are infecting patients to both optimize outcomes and minimize the risk of patient developing antibiotic or antibiotic resistance. Please join me in welcoming Dr. Dubberke.

(01:03): [Dr. Erik Dubberke]:   Overview of Talk. Hello. Thank you very much for the introduction and I'd like to thank the meeting organizers for inviting me to speak here today. It is a great honor and privilege. So this is my disclosure here. I've got a study that's paid for by Theriva Biologics in STEM cell transplant recipients.

(01:22): The learning objectives for my talk here today are for you to understand the risk for developing infections after stem cell transplantation and CAR T-cell therapy, and the recommended tests and procedures we use to monitor for and prevent infections after transplantation and CAR T-cell therapy.

(01:43): We will also discuss lifestyle changes to help you minimize your risk for infection after cellular therapies. And we're also going to discuss recommendations for revaccination and focus on COVID, flu shingles, and RSV.

(02:00): A quick disclaimer here. I'm just going to be covering general principles. When it comes to monitoring and preventing infections, there is often more than one approach. This is a rapidly evolving field and the recommendations frequently change. Typically, each transplant center will have their own general approach, and this general approach is often based on which infections they actually see at their center. And anything that they do for you might be modified based on your specific needs.

(02:38): Opportunistic infections are those that occur only, or more commonly, in people whose immune system is not working properly. I am a strong believer, the more informed you are in regard to your condition and management of such, the better your outcomes will be. I'm going to start with just some general infection concepts. First, here is the term opportunistic infection. This is an infection that occurs much more commonly or only in people whose immune systems do not work properly. So these are infections we don't normally see in people whose immune systems are working properly. And this is what a lot of my talk will be focused on here today, is how we prevent these infections after cellular therapies. Of note, those types of organisms that can cause infections in people whose immune systems are normally functioning can also cause disease in people whose immune systems are not functioning normally. Oftentimes they're more likely to cause infection and can be more severe as well.

(03:38): Opportunistic Infections can arise from viruses, bacteria or fungi.

 So a virus is an infectious particle. It has a shell, which is typically made of proteins and fats, and on the inside is DNA or RNA. By themselves, they're unable to make copies of themselves. They have to infect a living cell, and then they hijack the living cells machinery in order to make copies of itself. Then the cell dies as the new viral particles are released. There are treatments for many viruses, but some of them have no proven treatments.

(04:11): Bacteria are single cell organisms that can make their own copies. They live on our skin and in our intestines and they're present in soil and water. We have effective treatments for most of them, but resistance is becoming more common. And just so you're aware, when we talk about antibiotics, they're often referring more specifically to antibacterials. So antibacterials will kill bacteria, but they won't kill viruses or fungi.

(04:39): So fungi can be single cellular or they could have multiple cells, they can make their own copies. And we have Candida yeast that live on our skin and in our intestines. And there are molds that live in the environment, and in particular, they like decaying organic matter. There are proven treatments for the most common causes of fungal infections.

(05:05): Patients receiving transplant and CAR T-cell therapy should be screened for past and current exposure to infectious agents. Going into a transplant or CAR T-cell therapy, there's several things that we consider, one of which is your past exposures. And you may be asked questions about your occupation or hobbies, travels you may have done, many aspects of your diet, and possible animal exposures as well. And I'm actually going to be discussing these types of exposures in more detail and the potential infection risk when we're talking about your lifestyle modifications to consider after transplantation to help decrease your risk for infection. We will also assess you for any current infections you may have as we want to make sure that they're being properly treated before going into transplantation or CAR T-cell therapy. And sometimes we want to make sure those infections are completely resolved before we move forward with those therapies, which will suppress your immune system.

(06:01): Several viruses may already be in our bodies but only become activated when we are immunocompromised. There are many different types of infecting organisms that we screen for prior to moving forward with transplantation and CAR T-cell therapy. In the virus column there, those first four viruses are part of what's called the herpes virus family. So once we become infected with these types of viruses, they stay in our body for the rest of our life. If our immune system is functioning normally, typically they cause very few problems, but if our immune system becomes suppressed, they can cause more significant problems.

(06:37): Cytomegalovirus or CMV, used to be one of the primary causes of infectious problems after transplantation. That is a virus that about 50% of adults have evidence of past infection. Usually when we're infected with CMV, we're infected as a child, and it may not even cause any real significant illness as a child, but then it stays in you for the for the duration of your life.

(07:04): Varicella zoster virus, that's the virus that causes chickenpox and it's also the same virus that causes shingles. So most adults, so 99% of adults have either been infected with a chickenpox virus or have received a vaccine against the chickenpox virus. Later on in life it can reactivate and cause shingles.

(07:25): Herpes simplex virus is the virus that causes cold sores. 25 to 50% of adults have evidence of past herpes simplex virus infection. Of note, most adults with blood evidence of past infection with herpes simplex virus have never had cold sores. So even though you've never had cold sores, if you have evidence of past infection, you probably do have a virus in your body and it might be able to cause problems later on.

(07:54): Epstein-Barr virus is another virus that most adults have evidence of past infection. Over 95% of adults have evidence of past infection. Usually in adults it doesn't really cause problems after transplantation, but this is a more of a concern in children. So in children undergoing transplantation, if they have not had a past Epstein-Barr virus infection, if they get a new one after transplantation, then they could develop complications related to that infection.

(08:24): Some other viruses that we screen for prior to transplantation are HIV, hepatitis B, and hepatitis C. These are all viruses that can infect us for long periods of time before we know we have them. But we do have effective treatments for them, and we like to make sure that these get treated before moving forward with transplantation or CAR T-cell therapy.

(08:45): A nasal swab before transplant may detect such viruses and require rescheduling the transplant. We oftentimes will do a nasal swab for respiratory viruses a couple of days before your transplant is scheduled. And this is just to make sure that you don't have any active infections that have the potential to become worse after your immune system becomes suppressed when you receive your conditioning chemotherapy. So if you test screen positive for one of these viruses just before your transplant, they'll probably put it on hold until that infection resolves.

(09:13): Patients may also be screened for syphilis, tuberculosis, and various parasites before transplant or CAR T-cell therapy. Syphilis is a bacterium that many people aren't even aware that they become infected with it, but again, there's very effective treatments. So we like to screen for this before transplantation and get that treated if necessary.

(09:28): Some transplant centers, unfortunately have to deal with having bacteria resistant to antibiotics, and depending on your local transplant center, they may screen you for evidence that you're colonized with one of these bacterium, and this may impact how they decide to treat you later on if you develop signs and symptoms concerning for infection.

(09:51): Likewise with tuberculosis, if you have a history of having lived in the country where there's lots of tuberculosis or having you yourself been known to be exposed to someone with tuberculosis, they may screen you for that prior to transplantation and treat that as well.

(10:06): There are some parasites that we screen for. One is toxoplasmosis. We can get that either from handling cat poop or from eating undercooked meats. And that's a parasite we routinely screen for prior to transplantation.

(10:20): Strongyloides and Trypanosoma cruzi, those are parasites that are common in certain parts of the world but not in the US. So usually those are not screened for in the US unless you have a history of living in areas of the world where these parasites cause problems.

(10:39): Underlying medical conditions can also create risks for infection after transplant or CAR T-cell therapy treatment. So there are several different risks for infection after transplantation. One of which is your underlying condition for why you're having that transplant and past treatments you you've received for your underlying condition leading to transplantation. Many of these conditions are cancers of our white cells and as such, those types of white cells end up not working as well and putting you at increased risk for infection.

(11:06): The type of conditioning chemotherapy regimen they give you prior to transplantation will impact your risk for infection. The main difference here are between what's called myeloablative conditioning versus non-myeloablative conditioning. With myeloablative conditioning, you're more likely to have an infection early on after transplantation compared to non-myeloablative transplantation. But with non-myeloablative transplant conditioning regimens prior to transplantation, you tend to have more infections later on after transplantation compared to that myeloablative conditioning regimen.

(11:45): The type of transplant also impacts your risk for infection. So an autologous transplant is when they take your own stem cells from you and then infuse them back into you. So the risk for infection decreases much more rapidly after an autologous transplantation than after CAR T-cell therapy or allogeneic transplantation.

(12:08): So with CAR T-cell therapy, those current therapies, they're really designed to treat malignancies that impact B cells, and B cells are a part of our immune system. And so when you receive CAR T-cell therapy, that part of your immune system usually remains low.

(12:26): An allogeneic transplant is when you receive someone else's stem cells, and your risk for infection after an allogeneic transplant is higher versus CAR T-cell therapy or autologous transplantation. And when it comes to allogeneic transplantation, the source of the donor stem cells will have an impact on your risk for infection.

(12:47): The highest risk for infection comes after a stem cell transplantation with cord blood, and the risk is then lower with mismatched stem cells versus haploidentical stem cells. The risk is lowest with matched stem cells, a matched donor transplant. And this risk primarily has to do with the risk of developing graft-versus-host disease.

(13:11): Graft-versus-host disease can increase the risk for infection after transplant. Graft-versus-host disease is when those donor stem cells, which is someone else's immune system, is infused into your body. And then those immune cells, since they came from someone else, don't recognize your body and can start to attack your body. And that can both present like an infection but also is associated with having a higher risk for developing infection. And then the medicines we use to treat that graft-versus-host disease so further suppress the immune system and increase the risk for infection.

(13:46): We have several different immune defenses that are impacted by transplantation and CAR T-cell therapy, and I'm going to review some of these and the types of infections we tend to see when these are disrupted.

(14:00): Disruptions to skin and mucus membranes increase the risk of infection.  Our first line of defense against infection are our skin and mucus membrane barriers. So these just prevent bacteria from getting from the outside of us to the inside of us. So when these are disrupted, we tend to see infections related to those bacteria that we normally find either on the skin or in the mucus membranes.

(14:20): So when we have a disruption of the skin, we tend to see infections due to staph and strep bacteria. When we have disruptions of the mucus membranes of the mouth, we see infections due to strep bacteria and Candida yeast. And when we have disruption of the mucus membranes in our intestines or gut, we see infections due to gram-negative bacteria as well as the Candida yeast again.

(14:44): Lowered neutrophil and lymphocyte counts from chemotherapy increase the risk of several types of infection. Neutrophils are a type of white cell. This is the type of white cell we're often most concerned about right after we receive chemotherapy. This type of white cell is our first line of defense if bacteria gets beyond the mucus membranes or skin. When the neutrophils are low, again we tend to see infections due to those bacteria and yeast that like to colonize our skin and our intestines as well. Neutrophils are also important at protecting us against molds, and in particular protecting us against molds causing lung infections.

(15:22): So lymphocytes are another type of white cell and there's two main types of lymphocytes. There's B cells and T-cells. B cells are the type of lymphocytes that produce antibodies. And when those are low, we tend to see infections due to respiratory viruses and what are called encapsulated bacteria with the main one of concern being streptococcus pneumonia. When you receive the pneumonia vaccine, that's a vaccine that covers specific strains of this bacteria. When our T-cells are low, we tend to see infections due to viruses, molds, and parasites.

(15:58): After transplantation and CAR T-cell therapy, we see fairly predictable periods of infection risk based on the parts of our immune system that's being impacted by the transplantation or CAR T-cell therapy.

(16:12): Engraftment is that period when the donated stem cells start to make cells on their own. So the period before engraftment is that period after you receive that conditioning chemotherapy and your neutrophils become low and you receive the stem cells, and then engraftment occurs when those neutrophils start to come back. So in this before engraftment period, the main risk factors here are low neutrophils from chemotherapy as well as mucositis. That's when you get ulcers in your mouth and in your intestinal tract from the chemotherapy.

(16:48): Venous catheters can create additional risks of infection. Oftentimes you have what's called the central venous catheter. So that's the big catheter that goes into a vein in your neck or under your collarbone. So with these risk factors for infection, the types of infections we tend to see are bacterial infections due to bacteria that grow on our skin and in our gut as well as the Candida yeast. And with the neutrophils being low, we're also concerned for infections due to molds in the lung.

(17:17): Mucositis and mouth sores can reactivate the herpes simplex virus in all types of transplants. During this period because of the mucositis and mouth sores, we also tend to see reactivation of the herpes simplex virus as well. In this pre-engraftment period, we see similar risk for infection across all of the transplant types I've described, with autologous transplant, CAR T-cell therapy, and allogeneic transplant, with the main risks factor for infection being how long your neutrophils remain low and how bad the mucositis is.

(17:48): People receiving allogeneic transplants with donor cells are more prone to infections than those having autologous transplants (using their own cells). Once you've achieved engraftment and those neutrophils start to come back, then we start to see a difference in risk for infection across the different transplant types. Where with autologous transplantation, their lymphocyte function remains low but usually not low enough where we maintain any kind of medications to prevent infections. That's usually with allogeneic transplants. So again, those are the people who receive someone else's stem cells where the lymphocytes remain low enough that we are concerned about those opportunistic infections. And those are also the people that are increased risk for graft-versus-host disease. And again, graft-versus-host disease is a further risk factor for developing these types of infections.

(18:32): During this period, people often still have their central venous catheter placed as well as they might need additional blood products. So, during this period we tend to see infections due to skin bacteria from that central venous catheter. And then the opportunistic infections we see, most commonly see, are infections due to CMV, VZV, another virus called adenovirus. It's a respiratory virus that's more of a concern in children than in adults. We also see infections due to an organism called pneumocystis, as well as that parasite toxoplasmosis and also mold infections as well.

(19:10): After day 100, the risk for infection in allogeneic transplant patients is really related to how severe their GVHD is. If they have minimal graft versus hosts disease, then they remain at an increased risk for infections due to those encapsulated bacteria. And again, Streptococcus pneumonia is that main bacteria we're concerned about. However, if you have severe graft-versus-host disease and are needing to remain on multiple medications to control that, then your risk for infection remains similar as to that period in the engraftment to day 100.

(19:46): Infections are fairly common within 100 days of transplant and then infection risks decrease. This slide here is from a study looking at the number of infections people develop after an allogeneic transplant and looking at the impact of different sources of stem cells being bone marrow stem cells, or peripheral blood derived stem cells. So I like this graph because it gives the number of infections per 100 days at risk for infection. So if one person has 100 patient days at risk... Makes 100 days at risk for infection, excuse me, so based on that left part of the figure here between day zero and 100 on average we see about two infections per person. So that's what you could expect going through day 100.

(20:36): And actually, in the pre-engraftment period, most people will develop a fever during that period. And if you develop a fever, about half of those people will have a diagnosed infection during that pre-engraftment period. But then overall through day 100 on average we see about two infections per person. And then you can see as you get further out, that risk for infection goes down.

(21:02): There are many things we do to monitor for and to prevent infection during these different periods. What we do changes because the risk for infections changes over time.

(21:14): In that pre-engraftment period, we like to make sure that that big catheter, that central venous catheter is well cared for, and that we keep the skin as clean as possible around that to prevent infections from the catheter. Sometimes we give antibacterials to prevent infection while the neutrophil count is low, but not all centers do that. Also, some centers will give antifungals to prevent Candida infections and/or mold infections during those pre-engraftment period. But again, not all centers will do that. However, most centers, if not all centers, will give antivirals to prevent infections due to the herpes simplex virus as well as the VZV, varicella zoster virus, because they're very well tolerated and they're very effective.

(22:04): If you do develop a fever during this period, the typical protocol is that the nurse will draw blood cultures on you and start you on IV antibiotics as soon as possible. And usually, those antibiotics are continued until your neutrophils start to engraft. Also, for people undergoing an allogeneic transplantation, sometimes the hospitals actually have special hospital rooms that are specially designed to decrease your risk for mold infections. During this period, people can be hospitalized for several weeks if not a month or so. And so you have lots of visitors, and it's important during this period that people do not visit if they are sick. And also, it's important that visitors try to do their best to stay up to date on their vaccines to decrease your risk for infection.

(22:53): In the period between engraftment and day 100, there's several specific things we do to prevent infection.  For that HSV and VZV viruses, again, we usually maintain some sort of antiviral against them, and then usually it's either acyclovir or valacyclovir. These are very effective at preventing these viruses from becoming active and they're also very well-tolerated with very few side effects.

(23:21): Another infection that we actively monitor and try to prevent is CMV. Like I mentioned before, CMV used to be the most common infectious cause of problems after transplantation. There are two main approaches we use to prevent CMV. One is called preemptive. This is when we check your blood twice per week to see if the CMV virus is becoming active. And if it becomes active, we give you medicines to treat the CMV, we give you antivirals. The other approach is the prophylactic approach, and this is when we give a daily antiviral to prevent CMV from becoming active in the first place. Between both the preemptive and prophylactic approach, there are both pros and cons to both of these, and there's no clear winner, but we do know that they are equally effective at preventing CMV from causing disease in you.

(24:14): Pneumocystis can cause pneumonia and requires specialized medications. Pneumocystis is an interesting organism. We used to think it was a parasite based on how it looks and the types of treatments that are effective against it. But once we were able to sequence DNA, we found out that actually its DNA looks more like a fungus. Anyhow, this is an organism that can cause pneumonia and we routinely put people after an allogeneic transplant onto a medicine called trimethoprim sulfamethoxazole which is also called Bactrim or Septra to prevent this infection. If you happen to have a sulfa allergy or you develop complications related to Bactrim, we do have several alternatives available.

(24:55). If your pre-transplant blood test screens positive for toxoplasmosis, we like to make sure we have something that's effective at preventing that from becoming active as well. Fortunately, that Bactrim is effective against toxoplasmosis. If you have an intolerance to Bactrim or you're sulfa allergic, we do have other options to prevent toxoplasmosis. And we do have another option that's effective against both pneumocystis and toxoplasmosis, which is called atovaquone. So we could still cover both with one medicine.

(25:30): When it comes to mold, it's probably going to be more transplant-center specific as far as what they do for you. It's going to vary based on what other medications you're on and whether you have graft-versus-host disease. And also another factor to take into account is what your copay will be with your insurance. But usually if they put you on an antifungal in this period, it'll be some sort of antifungal that we call an azole antifungal because azole is at the end of the name of that antifungal.

(26:04): If patients have minimal or no GVHD and are off immunosuppressive drugs, their infection risk is much lower. After day 100, if you have significant graft-versus-host disease still requiring treatment, oftentimes we will continue the same approach to prevent infection as we were doing before day 100. If you have minimal to no graft-versus-host disease and you're off immunosuppression, your risk for infection is at its lowest point, but you are still going to be at increased risk for infection compared to people whose immune system is not suppressed.

(26:33): After day 100, some vaccinations may also be used to prevent infections. During this period to help decrease your risk for infection, this is when we recommend starting to vaccinate people. As I mentioned, we use a variety of approaches to try to prevent infection due to Streptococcus pneumonia. And this will probably vary from transplant center to transplant center as far as how they approach that.

(26:55): Lifestyle modifications like food safety can also prevent infections. There are several steps that can be taken to reduce infection risks from food sources. I mentioned earlier there's several lifestyle modifications that you can take to decrease your risk for infection after transplantation. One of which is food safety. I'm going to go over a lot here, but the overarching theme for you to remember is that it's okay to eat well-cooked food that's stored properly.

(27:16): What this means is that you have four steps to food safety with step one being clean. So you want to wash your hands before preparing food. And also, you want to make sure you thoroughly wash fruits and vegetables under running water.

(27:31): The second step to food safety is separate. So, you want to make sure you keep your meats separated from your vegetables. So, you want to have a separate cutting board and separate knives that you use for the meats from the vegetables and fruits, as the meats are where we are concerned there may be bacteria present that might infect you. Also, after handling the meat, you want to make sure you wash your hands right away before handling anything else.

(27:58): You then want to cook the food to the proper temperature, and then once you're done eating, make sure you get those leftovers put into the fridge.

(28:08): If you're not preparing food at home yourself, then you should feel free to ask whoever's preparing the food if they've been following these principles. And if you want to go out to a restaurant, you could check their health department rating.

(28:20): When you're cooking food, you do want to use a thermometer to check the internal temperature of what you're cooking. For meats that are in the form of chopped steaks or roast or fish, you want to cook it to an internal temperature of 145 degrees Fahrenheit. For ground beef and other meats and egg dishes, you want to cook it to 160 degrees Fahrenheit.

(28:42): For eggs, such as fried eggs, you don't need to use the thermometer to check the temperature of the egg. But once that yolk is fully cooked, when that yolk is hard, that means you've achieved a sufficient internal temperature of 160 degrees. For poultry as well as cured meats and leftovers, you want to heat those to a temperature of 165 degrees.

(29:05): Also, it is okay to eat fresh fruits and vegetables if they are washed. So even if that fruit or vegetable has a peel or a rind that you're not going to eat, you still want to wash it off before unpeeling it or cutting it. Because if there's bacteria on the exterior surface of that rind, you could contaminate the inside that you're going to eat as you cut into that fruit or vegetable.

(29:33): Several kinds of food and preparations should be avoided altogether to reduce the risk of infection. There are some foods that you're going to want to avoid, one of which is undercooked meats. So again, as long as you're cooking meat to the temperatures as I went over on the last slide, then, then, then that is fine.

(29:45): You probably want to avoid the deli counter at the grocery store. So you should not be eating deli or cured meats unless they've been cooked up to a temperature of 165 degrees. It's okay to purchase sliced cheese at the store, but you don't want to purchase cheese that's been sliced at the deli counter. And that's because those slicers that they use have been cutting the cured deli meats. And so bacteria from those meats can get onto that slicer, and that slicer probably has not been adequately disinfected before they cut the cheese. So you want to make sure if you get sliced cheese to make sure that it's pre-sliced in in the cheese case.

(30:25): Also, you want to avoid those prepared salads in the deli counter. So avoid those pasta salads, potato salads, chicken salads, and things such as that. You want to avoid unpasteurized dairy or raw meat products or raw milk products. You want to avoid soft cheeses as well as foods with mold. Multi-serve condiments at restaurants, you don't want to use those if they've been sitting there on the table for an unknown period of time. But if it's an unopened bottle, then that would be safe to use. You want to avoid eating dips that lots of other people are using as well, but what you can do is that you could take some of that dip off and portion it off for yourself before everyone else starts to use that dip. You want to avoid fresh fruits and vegetables that you did not wash and/or are multiple use such as a salad bar. Raw sprouts should not be eaten even if they're well-washed, because bacteria can get into the inside of the sprouts. And you also want to avoid cold brew teas.

(31:31): Avoiding new pets for the first year after transplant is advisable. For animal safety, you want to avoid new pets in the first six to 12 months after your cellular therapy. This is because juvenile and stray animals, if you're adopting a pet, are more likely to have organisms that can infect you. And also when you bring a new pet into the home, it's when you're more likely to have bites and scratches as well. So again, you want to avoid new pets for that first six to 12 months after your transplantation or CAR T-cell therapy.

(32:03): Vaccinations and flea and tick preventatives for pets are also advisable. And then if you do have a pet at home or want to bring a pet into the home after that period, you want to make sure they stay up to date with their vaccinations, and you use flea and tick preventatives for your cats and dogs.

(32:16): Many other animal exposures should be avoided to minimize infection risks. Things you do not want to do after your transplantation or CAR T-cell therapy are to clean cages or tanks. You should not be handling feces or droppings, and you should not be touching reptiles, poultry, livestock, game, or exotic pets. If you are unable to avoid this, say such as your occupation, if you're a veterinarian or work in a veterinary clinic and you have to do something like this, then you should be wearing gloves and thoroughly wash your hands afterwards. And if you're doing something that's going to generate dust or an aerosol then you also want to wear an N95 mask during this process. And then I'm not going to go over this table here in any detail, but these are the main organisms of concern with all these different animal exposures.

(33:04): People should be cautious about gardening, outdoor sources of dust, tick-borne illnesses and swimming in natural bodies of water. So, some additional exposures to be mindful of. So, if you like gardening, that's fine. But you must remember there's mold in dirt. So, you want to make sure you're wearing gloves and thoroughly wash your hands afterwards.

(33:15): It's really best to avoid construction, especially demolition work where there's going to be a lot of dust generated. But if it's not possible to avoid that, then you should wear an N95 mask. The concern here is with molds infections.

(33:31): If you're going to be outdoors hiking, you want to be mindful of tick-borne illnesses. Make sure you use DEET, wear long pants and sleeves, and do tick checks afterwards.

(33:41): You should always check with your transplant center when it's safe to go swimming afterwards. Be aware that swimming in natural bodies of water have more bacteria than say, in a pool. Double check with your transplant center before you go swimming.

(33:58):  Caution around crowds is important to minimize infection risks. It's important to try to avoid crowds if you can, especially during flu and pneumonia season because of the risk for respiratory viruses. If you're unable to avoid crowds, then you can wear a mask to decrease your risk. And also, this is why it's important to keep up to date with your vaccination to avoid, to decrease your risk of having problems if you happen to get one of these viruses.

(34:22): Municipal drinking water is generally safe and you don't need to do any additional testing and it's safe to drink, but if you have well water, you want to double check within your region what the recommended testing is and make sure it remains up to date and checked as needed. If you're unable to do that, then you'll want to boil your water before drinking it.

(34:49): Before international travel, check the CDC website for infectious risks in various destinations. Concerning international travel. So, first thing to do before you go on international travel is to double check with your transplant center if it's okay for you to go. And if you get the okay, start to investigate your travel risk right away.

(35:05): The CDC actually has a very nice travel website where you can look up specific countries and it'll let you know what sort of infectious risks there are. If you're going to a developing country, you should be seen at a travel or infectious diseases clinic ahead of time. And the sooner you know you're going to travel, the better it is to go get seen at one of those clinics, because it may be recommended to receive a vaccine that's not part of our routine vaccines. But might require multiple doses over several months. So you want to give yourself enough time to get those vaccines. Plus, there may be other medications they recommend you take to prevent infections.

(35:47): Revaccination after transplant should follow recommended schedules from six months to two years  posttransplant. For vaccination, it's generally recommended to start revaccinating after transplantation about six to 12 months afterwards. However, with live viral vaccines, those should be avoided for two years. So some examples here are the measles, mumps, and rubella vaccine, and the chickenpox virus or VariVax, that's another live viral vaccine. And it's recommended to avoid for two years after transplantation. And for people with graft-versus-host disease, if you are remaining on immunosuppressants, it's generally recommended to avoid these vaccines in general. But again if you have any questions you should double check with your transplant center.

(36:25): Even if you've received a prior vaccine series or been infected with one of these organisms, it's recommended to complete that full vaccine series again after transplantation. Although your immune response and protection from these vaccines might be lower versus the general population, these vaccines still will decrease your risk of having a bad outcome if you happen to get one of these infections.

(36:48): Household contacts and visitors should do their best to stay up to date with their vaccines as well to decrease their risk from getting these infections and if they get infected to decrease the risk of spreading it to you. Of note, if you have a household contact or a visitor that's had a live viral vaccine, you should double check with their transplant center what you should do because there may be a period where you should avoid close contact with that person after that live viral vaccine.

(37:19): Shingles vaccination is something that's become available in the last several years for transplant recipients. Shingles used to be one of the most common causes of infection after day 100, and that's around the time when the antiviral prophylaxis was stopped. Again, it's the same virus as the chickenpox virus.

(37:39): The first vaccine that became available was Zostavax, which was a live viral vaccine. So we couldn't really use it in this period when people are at highest risk. But now there's the Shingrix vaccine available, which is made of viral proteins, and it is recommended for all immunocompromised people that are at least 18 years of age and who have a history of chickenpox or chickenpox vaccination. And it's okay to give this while you're still receiving your prophylaxis.

(38:08): Regular influenza vaccines are also recommended for transplant recipients. Influenza vaccines are updated every year because the influenza virus continues to evolve. And so, these vaccines only provide us about six months of protection. There are several types of vaccines available. One is an inactivated virus grown in eggs, and that's the most common type of vaccine available for influenza. If you happen to have an egg allergy, there are vaccines available that are made of viral proteins grown in cell culture and so those are safe for you to receive if you have an egg allergy. Of note, there is a live viral vaccine for influenza called Flumist. And again, you want to avoid this, and your household contact should avoid this influenza vaccine as well.

(38:48): You may hear in the news some years there might be a bad match between the vaccine and the circulating strains of influenza, but still though, even those bad matches still provide protection against bad outcomes due to influenza. It is recommended to get influenza vaccines even if it's a bad match, and you cannot get influenza from the influenza vaccine.

(39:12): COVID-19 vaccination and boosters are recommended for transplant recipients. For COVID-19 vaccination, we're still learning about this virus but one thing we do know is that it's a very tricky virus and it's very good at evolving and avoiding our immune system. And right now, it seems that most of our vaccines provide about six months of protection before the COVID virus is able to evolve enough to avoid that immunity that we've built up with that prior booster. And again, these boosters do protect against bad outcomes. There are two main types of vaccines here. There are the mRNA vaccines, which are the Moderna and the Pfizer vaccines. If you prefer a more traditional type of vaccine, there's the viral protein vaccine available, which is the Novavax.

(39:58): Transplant recipients should check with their doctor about RSV vaccinations. RSV vaccinations became available in the last year. They're approved for use in people that are at least 60 years of age and people who are pregnant. But currently there's no official recommendations for non-pregnant people less than 60 years of age. So, there's no recommendations yet for immunocompromised people transplant recipients that are less than 60 years of age. So, this is something to double check with your transplant center if it's something they recommend. And then you'll have to check to see if your insurance company will help cover that as well. This is a viral protein vaccine, so it's safe to receive otherwise even if you're immunocompromised. Right now, it's recommended just as a one-time dose, so it provides protection out to two years, but that how well it protects you decreases over time. So at some point there may be boosters recommended for this vaccine as well.

(40:54): So in summary, transplant and CART T-cell recipients go through predictable stages of infection risk and there's several things that we do to help protect you against these infections, and we monitor for these infections as well. There are steps that you can take also to decrease your risk of infection after transplantation and those are summarized here.

(41:18): And then also it is recommended to be revaccinated after transplantation and you will receive the full vaccine series. There is a shingles vaccine which is safe for transplant recipients, which is the Shingrix vaccine. It's recommended to receive the influenza vaccine every year. And with COVID-19 and RSV we're still learning about these viruses, but again, it's advisable to receive these vaccines as they become recommended. And with that, we will open up the Q and A session.

Question and Answer Session

(41:52): [Jordan Sexton]:  Fantastic, thank you very much Dr. Dubberke for an excellent presentation. We are going to now begin the Q and A session. If you have a question for Dr. Dubberke, please use the chat box on the left side of the screen to submit your question, and we're going to try to get through as many questions as possible. Starting with our first question. If my basement is damp and at times mold can be seen, should I be concerned? I've always just cleaned the walls with bleach.

(42:21): [Dr. Erik Dubberke]:   Yeah, so as long as you are not doing anything to aerosolize that mold or the mold spores per se, then your risk really should be minimal. I think what you're doing there, spraying it down with bleach, is a good way to reduce the burden there and decrease your risk. If you were to do, try to do some sort of mitigation of the area so trying to fix the problem so it doesn't keep getting wet, you might want to, you know, depending on how your house is designed and what the airflow is like, you might want to consider moving out of your house temporarily while that demolition work is happening as that's when the mold spores will be released.

(43:04): [Jordan Sexton]:  Our next question is someone who wants to know, how long does it take for your immune system to rebuild after transplant? Does it ever really get back to normal? They still isolate a lot, no concerts or indoor parties or large gatherings, and wear a mask in public after two years. And similarly, another person asked they’re 10 years post-transplant, do they still need to be concerned about infections?

(43:28): [Dr. Erik Dubberke]:  Yeah, a lot of these questions are related to the specific factors related to your transplant and how you've done after the transplant. But one thing is true, your immune system will never work as well as someone who hasn't gone through everything that you've gone through. That's related not just to the transplant procedure, but like I mentioned over the course of my talk, your underlying condition is going to affect your immune system function as well. Some of that is going to persist even when you're in remission. As far as your individual risk, when you're a year out, two years out, three years out, kind of depends on everything else going on.

(44:13): If you're an autologous transplant recipient, so you received your own stem cells back, your risk is pretty minimal. If you have graft-versus-host disease, and you're off of immunosuppression and have very little graft versus hosts disease, again, your immune system is you know, probably not functioning as well as that autologous transplant person, but you're doing pretty good, and your risk is pretty low.

(44:39): If you are having graft-versus-host disease on multiple medications, your immune system is still pretty suppressed, and you are going to be at increased risk for infection. So as far as, if you're doing otherwise kind of well and you know, your immune system is not quite back completely to normal, if you're going to be in a really crowded indoor area and it's cold and flu season, it probably is advisable to go ahead and wear a mask still in that setting. Make sure you remain up to date on your vaccines. Those will all decrease your risk of having complications if you happen to get one of these infections.

(45:18): [Jordan Sexton]: Is it safe to have facials, manicures, or pedicures after a stem cell transplant or bone marrow transplant?

(45:25): [Dr. Erik Dubberke]:  Yeah, so it depends on the specific type of treatment you're receiving there. One thing is to double check the Department of Health rating of where you're going. You want to make sure they've been reviewed by the Department of Health and that they are sterilizing their equipment properly. People can get infections after manicure or pedicure, even if your immune system is functioning normally. But as long as they're taking proper measures to sterilize their instruments between patients, then it should be safe to receive that. But again, I would clear that with your transplant center first before you go ahead and do that.

(46:07): [Jordan Sexton]:  This person wants to know, do you have to retake baby vaccines, shingles, and pneumonia after CAR T therapy?

(46:17): [Dr. Erik Dubberke]:  With CAR T therapy, this is a newer treatment and it's not clear exactly what we need to do at this point. And so, you're going to see some variability from center to center in regard to what they recommend. That would be something just to double check with your center to see what their approach is. They might test you first against some of these infections to see if you have any antibodies against them. And if not, then they might recommend going ahead and vaccinate. If you do have detectable antibodies, then they may not decide to vaccinate.

(46:55): [Jordan Sexton]:  If you have to avoid, or if you should avoid cold brew tea, should you also avoid cold brew coffee?

(47:04): [Dr. Erik Dubberke]:  My wife actually, I went over this talk with my wife and, and in part because actually her dad, my father-in-law, actually had AML and underwent an allogeneic transplant himself. And so I thought she would be a good sounding board for my talk, and she came up with that question. So the cold brew tea, so tea leaves are known to have mold spores on them. So cold brewed teas, if you brew a tea in hot water, that hot water will kill the mold spores. So cold brew teas, the mold spores are not killed, and it is described that people have gotten mold infections from cold brew teas. Coffee's different in that the beans have all been roasted to a degree where any mold spores that may have been on them before the roasting get killed. So it's okay to have cold brewed coffee.

(47:59): [Jordan Sexton]:  I'm not sure if this person is looking for an excuse but they'd like to know if they should not mow the grass while their immune system is compromised.

(48:09): [Dr. Erik Dubberke]: Yeah. It's probably best to avoid being out there yourself mowing the lawn for probably the first three to six months after your transplant. And again, this is going to be a little specific related to if you underwent an autologous transplant or an allogeneic transplant. Definitely in the fall when there's lots of leaves, the leaves, the dry decaying leaves will have mold spores on them when it gets dusty when you're mowing them, that you're dispersing mold spores with that. So that would be a time to be extra cautious and maybe even wear an N95 mask. Even if your transplant center says it's okay for you to mow the lawn if there's a heavier burden than normal of potential mold spores because it's dusty and dirty and there's lots of leaves, what-have-you, then you could wear a mask during it as well.

(49:06): [Jordan Sexton]:  That's good to know. If you have GVHD, can you ever get the MMR vaccine?

(49:12): [Dr. Erik Dubberke]:  At this point once you're two years out from transplant, and if you remain on immunosuppressants for graft-versus-host disease, it is recommended to not give the MMR. You know, if there is an ongoing measles outbreak in your community, then a lot of people may consider giving the vaccine at that point, again, depending on how immunosuppressed you are. Because the risk of the vaccine might be lower than the risk of you getting measles in your community if there's an ongoing outbreak. But in general, if you're on immunosuppressants for graft-versus-host disease beyond two years, then it is still recommended to avoid the MMR.

(49:58): [Jordan Sexton]: About your recommendations for food avoidance guideline's long term. This person wants to know in particular should they be avoiding foods like over easy fried eggs and deli meats permanently.

(50:14): [Dr. Erik Dubberke]:  I'll keep using the disclaimer. It kind of depends on your personal situation. If you have received an autologous transplant or CAR T-cell therapy or allogeneic transplant and you're off immunosuppression, then it's probably okay for you to eat those again. But if you remain immunosuppressed, if you're within six months of transplant, if you are on medicines for treatment of graft-versus-host disease, then it's advisable to continue that avoidance.

(50:49): [Jordan Sexton]:  Do you work with CAR T-cell survivors, and they have B-cell aplasia. This person is almost four years out and still has B-cell aplasia and has to do weekly IV subcutaneous or Ig subcutaneously at home. If you do have patients with B-cell aplasia, have you had any that have recovered from the B-cell aplasia? Do you do anything in particular with them beyond IVIG?

(51:15): [Dr. Erik Dubberke]: As an infectious diseases doctor, I'm not following all the patients after their therapies. I get asked to see patients if they have a question about past exposure and whether or not they need to receive any special kind of treatment or if they develop an infection. So, if someone is doing well and their B cells have recovered, they're probably not going to be someone that I would see. So unfortunately, I'm not able to answer your question directly. But many times, for a lot of these conditions, people receive lots of Rituxan ahead of time. Sometimes people who have received lots of Rituxan even in the distant past. And same with CAR T-cell therapy, some of those people never fully recover their B-cell function.

(52:06): [Jordan Sexton]:  Are you able to get the shingles vaccine if you're under 50? And has this guidance changed recently, if so?

(52:14): [Dr. Erik Dubberke]:  The shingles vaccine, the Shingrix vaccine, I'll be more specific because there's the live viral vaccine, which you should avoid. But the Shingrix vaccine, yeah, so it is recommended for people under 50 if you're immunocompromised. So it is recommended for people 18 years of age and older if you have an immune compromising condition. So yes.

(52:38): [Jordan Sexton]:  How long do you have to be on Bactrim after CAR T as well as IVIG and Acyclovir after CAR T?

(52:46): [Dr. Erik Dubberke]:  Yeah, again, this is, you know, CAR T like I said earlier to another question, it's a newer therapy and we're still learning. Sometimes it's going to be related to your underlying condition, and what maybe infections you've had up until your CAR T therapy or even after your CAR T-cell therapy. So an example I'm going to give here is sometimes lymphoma, by itself, is a risk... Some people develop pneumocystis pneumonia with lymphoma. Even, you know, if those people get into remission so there's no evidence of lymphoma, even just with standard chemotherapy, they remain at increased risk for pneumocystis pneumonia and those people sometimes are recommended to remain on the Bactrim.

(53:36): Some of these questions get into kind of specific question, specific issues related to your situation that's difficult for me to answer specifically in this Q and A session. But for a B-cell, CAR T-cell therapy that's directed against say, lymphoma, especially if you have a history of pneumocystis, then yes, I could see why or that a center might recommend continuing Bactrim indefinitely in that setting.

(54:11): [Jordan Sexton]:  Is there any guidance or latest information about re-vaccination for major diseases following CAR T or is it still in the process of figuring it out?

(54:21): [Dr. Erik Dubberke]:  Yeah, we're still learning. And you know, again, some of these are going to be center to center-specific recommendations. Some centers will say that they check your antibody levels per some of the prior questions. If you're still needing IVIG, you're not making any antibodies, they may say, "Well, it's not even worth bothering to vaccinate you against the..." You know, vaccinate you in general just because your body's not making any antibodies at all. So we're still learning after CAR T-cell therapy.

(54:59): [Jordan Sexton]:  Okay. Have you seen any patients remain on acyclovir as a lifetime medication or is there any length or cutoff that a person can remain on it?

(55:12): [Dr. Erik Dubberke]:  As long as you're tolerating the Acyclovir or Valacyclovir, there's very low risk to it to you to remain on it for a long period of time. Again, if you yourself have had issues with either the herpes simplex virus or varicella zoster virus that caused significant problems or they kept coming back again and again that might be why they've decided to continue that for you. But there's no known cumulative risk over time with any of those medications.

(55:51): [Jordan Sexton]: One person wants to know if we're still learning about COVID, might it be wise to avoid this vaccine?

(55:58): [Dr. Erik Dubberke]:  No. I mean, literally, hundreds of millions of people in the United States and even more across the globe have received COVID-19 vaccines. And what that experience has taught us is they are very safe. The mRNA vaccines, they are a newer technology to use in people, but those actually have been under development for 30 to 40 years. And there actually have been several other infections for which mRNA vaccines were being developed for, but then COVID came along and that is actually a kind of a really neat way to make a vaccine and a way to make a vaccine that you could change quickly as an organism evolves. So the vaccines are safe, definitely safer than not being vaccinated and getting a complication due to COVID-19.

(56:57): [Jordan Sexton]:  I think we have two minutes left, so this will probably have to be our last question. This person is concerned about the increased number of cases of measles. Do you know of any work on non-live vaccines against measles? And do you have any thoughts on minimizing the risk against measles?

(57:15): [Dr. Erik Dubberke]:  Yeah, I am not aware of any ongoing research in a non-live measles vaccine. The MMR vaccine, actually, it's very effective for those people that that can receive it. And this is really a newer thing where we have more and more people that can't receive it. But probably a good thing is we're probably we're nowhere near a stage where a new vaccine would be able to be properly studied to see if it actually works just because there aren't enough measles cases at this point. As far as what you can do, one thing is to oftentimes these measles outbreaks are associated with a specific exposure at an event. And so you can keep tabs on that in the news as far and the CDC website as far as what the events are and the extent of that exposure. And based on that, you can talk to your transplant center if you feel you've been exposed, and then what you should do next.

(58:31): [Jordan Sexton]:  Closing. Well, thank you so much Dr. Dubberke. I'd like to thank you on behalf of BMT InfoNet and our partners for your incredible presentation and great answers to the questions of the audience. And thank you to the audience for those great questions. Please contact BMT InfoNet if we can help you in any way and enjoy the rest of the symposium.