Infections after Transplant

Infections after Transplant 

Wednesday, May 3, 2023

Presenter: Jennifer Cuellar-Rodriguez MD, National Institutes of Health Transplant and Cellular Therapy Clinical Program

The presentation is 32 minutes long followed by 26 minutes of Q & A.

Summary: Several types of infection can occur after a stem cell or bone marrow transplant and can complicate recovery for patients. This presentation describes the infection risks during the posttransplant period, therapies to treat them, and some measures to prevent them.

Highlights:

• Infection risks from stem cell transplantation can be divided into three periods: pre-engraftment, early engraftment, and later engraftment. Patients are at highest risk for infection in the pre-engraftment period when their immune system is severely compromised.
• In the early engraftment period, as the immune system begins to recover, preventing graft-versus-host-disease and opportunistic infections becomes a major concern.
• Posttransplant infections may be prevented by three main strategies: preventive medicines, vaccines, and lifestyle modifications.

Key Points:

(01:47): A pre-transplant evaluation assesses an individual’s risk of getting infections after transplant.

(05:42): Infections are common early after transplant but become less common over time.

(11:28): After transplant, when patients can return to their home community, they have greater exposure to respiratory viruses, gastrointestinal viruses, and infections associated with food and water.

(12:47): Transplant recipients who relapse or who have graft-versus-host disease (GVHD), have an increased risk of infection.

(13:17): Posttransplant infections may be prevented by medications such as antibiotics, antifungals, and antivirals; vaccines, and lifestyle modifications.

(18:16): Following food safety recommendations is crucial for transplant recipients with a weak immune system.

(22:42): Pets can have many emotional benefits for transplant recipients, but they can also carry a significant number of bacteria or parasites that can be harmful.

(25:26): Outdoor activities have many health benefits for transplant recipients. However, precautions should be taken when doing outdoor activities including gardening and yard work.

(26:18): When planning to travel after transplant, consult your transplant team about whether it is safe, and precautions you should take to reduce your risk of infection.  

(29:41): Respiratory viral infections are common after patients return to the community. Frequent handwashing, minimizing contacts, and wearing a mask are important preventive measures.

Transcript of Presentation:

(00:01): [Lynne Spina]: Introduction: Hello, welcome to the workshop Infections after Transplant. My name is Lynne Spina and I will be your moderator for this workshop.

(00:11): It's my pleasure to introduce our speaker, Dr. Jennifer Cuellar-Rodriguez. Dr. Cuellar-Rodriguez is the director of the Transplant Infectious Diseases Consult Service at the National Institute of Allergy and Infectious Disease in Bethesda, Maryland. She works closely with various National Institutes of Health to implement allogeneic transplant and gene and cellular therapy protocols.

In addition to clinical care, she provides educational support not only for oncology and transplant fellows, but also for mid-level providers, and is an active member of the committees that develop institutional guidelines for the prevention and management of infections and cellular therapies. Please join me in welcoming Dr. Cuellar-Rodriguez.

(01:12): [Dr. Jennifer Cuellar-Rodriguez]: Overview of Talk. Thank you for that kind introduction and the invitation to be part of this symposium. As was already mentioned, I'm going to be discussing infections in transplantation and, more importantly, what things we can do to decrease the risk of acquiring these infections.

I have nothing to disclose.

(01:31): These are the specific topics I want to discuss today. The pre-transplant evaluation, when infections happen after transplantation, who is at increased risk of infection and again, more importantly, how to prevent this infection.

(01:47): A pre-transplant evaluation assesses an individual’s risk of getting infections after transplant. We know that transplantation, in general, is associated with an increased risk of acquiring infection. In the pre-transplant evaluation, we're trying to understand an individual's specific risk for getting infections and make the transplant safer for them. We know the world is full of microbes, and a patient may have been exposed to certain microbes that can cause problems as we proceed to transplantation. Therefore, we will ask about specific potential situations that make that individual's risk of infection higher.

(02:29): We'll ask about travel, hobbies, activities. We'll ask about particular gastronomic preferences that have been associated with difficult-to-treat infections. We will ask about your pets or animal exposures. Most of these questions are not because we are nosy. We just want to understand what your risk of getting different infections is as you go through transplantation.

(02:53): Any active infections should be treated before stem cell transplantation. We will also try to identify any active infections that you have before the transplant, give you treatment, and if it's possible, cure them. If this is not possible, at least have them under control before proceeding to transplantation.

(03:08): Because we will be using many antimicrobials as we proceed through transplantation, we will also ask about drug allergies. We will order blood tests and imaging tests. Many of these tests are designed to understand which organisms you may have been exposed to, without knowing it, before going to the transplant.

(03:36): Transplant patients should also be assessed for opportunistic infections that may arise with immunosuppression. For example, let's take cytomegalovirus or CMV. This is a virus that most adults have been exposed to either during their childhood or adolescence. In the United States between 50 to 70% of all adults have been infected with CMV. CMV is one of those viruses that, once you get infected, you're always infected, but we don't get sick from it because our immune system prevents this from happening. However, when our immune system is weakened or not working properly, mostly due to the chemotherapy or the drugs that are used to prevent graft-versus-hosts disease, these microorganisms see an opportunity to cause disease. We call them opportunistic infections.

(04:30): So, we'll try to identify many of these prior infections that you likely won't be aware of. We'll look for other specific infections that you may have encountered because of specific exposures. For example, if you come from a country where there's a lot of tuberculosis, we'll make sure you don't have, or have not had, any contact with tuberculosis throughout your lifetime.

(04:59): Not only do the microorganisms that you've been exposed to increase your risk of infection, but the risk of infection varies significantly with the type of transplant you're receiving, and the specific disease led to the transplant. If you're an allogeneic transplant recipient, the type of donor we find for you will also impact your risk. We will try to adjust all the infection-prevention measures accordingly for all these risk scenarios.

(05:27): If you had many infections during chemotherapy prior to going to transplant, you are more likely to get other infections after transplant.

(05:42): Infections are most common early after transplant but become less likely over time. When do infections occur after transplant? Once I'm transplanted am I always at risk of an infection? Well, we are all at risk of an infection but certainly the risk for transplant recipients is higher. But the risk is not the same throughout time. We know infections are most common early on after transplant and decrease over time.

(06:09): This graph shows the number of infections in different time periods. So the first two graphs on the left side correspond to the time between the infusion of the cells until three months after transplant or day 100. This is a period when the risk is significantly higher, regardless of what type of transplant you had. Everyone, in this period of time, is at greater risk.

(06:40): If we look at the next two bars, that's the time between three and six months after transplant. The risk is still significant at that time point, but it's less so than the first three months after transplant.

(06:54): If we look at the next six months after transplant, between six months and one year, we see that the risk is still there but it's lower than the previous six months. And once we pass the first two years after transplant, the risk decreases significantly if everything went well, meaning there is no recurrence of the disease, there is no graft-versus-host disease and the patient is no longer receiving any immune suppression. However, if we compare the number of infections that occur after transplant, it's still higher than for someone who never received a transplant.

(07:40): Infection risks from stem cell transplants can be divided into three periods: pre-engraftment, early engraftment, and later after engraftment. To prevent infections and to treat them very early, it's helpful for us to think of the periods of increased risk for infections as three big groups. The first risk period is the time before engraftment, meaning after the infusion of the stem cells, before those cells come back [begin producing healthy cells]. The next period is between the recovery of those cells until day 100. And the last period, late after engraftment, is after day 100.

(08:16): Patients are at highest risk for infection in the pre-engraftment period when their immune system is severely compromised. In the first period, prior to the recovery of blood cells, the blood cell counts are expected to be low, so the red cells, the platelets, the white blood cell counts. The white blood cell counts are also called leukocytes and these are the ones that we infectious disease doctors pay more attention to. The two subsets of leukocytes that we focus on to determine interventions to prevent infections are the neutrophils and the lymphocytes.

(08:56): Why do the infections happen so often at this period of time? At this time, you will most likely be in the hospital or visiting the hospital very, very often. Usually, you'll have all the side effects from chemotherapy happening to you like mucositis, which is destruction of the lining of the barrier from your oral mucosa in your mouth, your intestinal tract, all the way to your anus. We have a lot of bacteria that live in our mouth and our intestines. If we destroy this barrier with chemotherapy, then the bacteria that normally lives in our mouth and our gut can go into our blood and cause disease.

(10:00): This is why, when your counts are very, very low, when you're neutropenic, we start antibiotics very, very quickly if you develop a fever. We'll likely also get blood cultures and we worry about this scenario. So, if you are at home and your counts are low, and you know you're neutropenic, it is extremely important that you seek care very quickly, even if the fever seems mild. Other infections that we can see in this time point are infections from the lines or the catheters, and we can have pneumonia or colitis.

(10:40): In the early engraftment period, preventing graft-versus-host-disease (GVHD) is a major concern. The second time period starts right after those neutrophils start to come back, or neutrophil engraftment. During this time, until day 100 after transplant, especially if you had an allogeneic stem cell transplant, we're trying to prevent graft-versus-host disease. So, immune suppression is still significant in this time and the lymphocytes, which are the ones that usually protect us from viruses and some parasites and some fungi, are still very, very low. So opportunistic infections such as CMV can happen. We'll give you medicine to prevent this infection.

(11:28): Once patients can return to their home community, they have greater exposure to respiratory viruses, gastrointestinal viruses, and infections associated with food and water.  Finally, once both the neutrophils and lymphocytes start to recover, then our immune system is more prepared to deal with infections. Patients, at this time point, can be divided into two large groups of patients. The first group includes patients who are autologous transplant recipients and who have had good recovery of their cells and control of the disease that made the transplant necessary. It also includes those allogenic stem cell transplant recipients who never developed graft-versus-host disease and who also have good control of their disease.

(12:14): These patients usually are no longer on immune suppressants or the immune suppressants are starting to decrease significantly. They're starting to be transfusion-independent and have fewer visits to the hospital. They are now in the community more often and are less often in the hospital. This group of patients now gets exposed more to respiratory viruses, gastrointestinal viruses that children can take home, or infections associated with food and water.

(12:47): Transplant recipients who relapse or have GVHD have an increased risk of infection. The second group of patients is those whose disease came back or who have graft-versus-host disease and are therefore still on significant immune suppressants or still receiving chemotherapy. These patients have an increased risk of infection, like the prior time period. The risk is still there and they still need to be protected against these opportunistic infections.

(13:17): Posttransplant infections may be prevented by mediation with preventive medicines, vaccines, and lifestyle modifications. So now we know that infections happen after transplant, what can we do to prevent these infections? There are three main strategies that we use to prevent these infections: mediation, vaccines and lifestyle modifications.

(13:34): Preventive medicines include antibiotics, antifungals, and antivirals. Preventive medicines, called antimicrobial prophylaxis, are medicines like antibiotics, antifungals, or antivirals that are used to prevent infections caused by bacteria, viruses, and fungi. Some of these medications will be continued even a few months after all immune suppression has been stopped, so these may be the last medicines that you need after a transplant.

(13:59): If you're having difficulty taking your medicines, talk to your doctor. We know that if you're having a hard time tolerating many meds, it can seem easy to just discontinue a medicine or start skipping doses. Please let us work with you. If we know you're having trouble with a specific medicine, there may be alternatives to that medicine, or there may be alternative schedules that are easier to tolerate. Let us work with you to make sure you get all the medicines you need.

(14:41): After transplant, patients need to repeat their childhood vaccinations, except those containing a live virus, usually starting three to six months after transplant. Vaccinations. Vaccines train our immune system to fight infections. After transplant, our immune system loses most of the knowledge or memory that it has accumulated through a lifetime on how to best fight common infections. Therefore, after transplant we need to be re-vaccinated, as if we were small children.

(15:02): Vaccinations typically start around three or six months after transplant. However, there are some vaccines that may be harmful for us, specifically during the first two years after transplant. These are vaccines that are made of live, debilitated viruses. Always discuss with your doctor which vaccines you're supposed to and can receive.

(15:32): This is a sample schedule of when vaccines are given after transplant. Each transplant center may have a slight variation of this schedule, and depending on how long it has been since your transplant or the type of transplant you received, some of this may or may not be recommended.

(15:49): Many of those on the white background can be given very early, starting between three and six months after transplant. Those on the orange background, like the measles vaccines, are some of the live virus vaccines that should not be given to any transplant recipient during the first two years after transplant. They are given, instead, when your immune system is ready to handle live, debilitated viruses, assuming you are not on any immune suppression.

(16:28): Lifestyle modifications may also prevent posttransplant infections. The third intervention is lifestyle modifications. Remember, the objective of transplantation is to not only to restore health, but also to restore the quality of life. These lifestyle modifications are not meant to be so restrictive that the quality of life is poor. However, the earlier it is after-transplant, the stricter we suggest you be regarding these recommendations.

(16:57): Keep in mind that as an infectious disease doctor, I'm going to recommend these same lifestyle modifications to anyone that's trying to prevent infection. It's all about trying to reduce the risk. If you're on significant immune suppression because you have graft-versus-host disease, or it's very early after transplant, we suggest that you be very good about following all these recommendations. I'm going to try to discuss all these scenarios except for safe sex because it's my understanding that there is a talk on reproductive health. However, I do want to mention that safe sex includes using some type of barrier, like a condom, to prevent sexually transmitted diseases.

(17:46): State health departments, as well as the Centers for Disease Control (CDC) publish information on their websites about area food safety issues with recommendations on how to prevent infections.  So, let's discuss food safety. Transplant recipients and their families should pay particular attention to any local recommendations regarding outbreaks. Subscribe to your state health department's email alerts or make it a habit to review their website frequently or the CDC (Centers for Disease Control) website. These are sites that are usually up to date on what the current recommendations are.

(18:16): This graph comes from the CDC website which is down here. I understand you have access to these slides so you can go to this website at any time. Some of the recommendations are to always wash your hands before preparing food. Also, disinfect and wash the surface where you will be preparing food. Germs survive in many places for a prolonged period of time. Use separate cutting boards for raw meat or poultry and seafood. Using the same board can spread bacteria to ready-to -use foods, so it's important to keep them separate.

(18:55): Ensure that food has been cooked to an internal temperature that is high enough to kill germs and keep you safe. Again, this website has specific suggestions about the temperature different types of meats should be cooked to. The internal temperature that needs to be reached for pork or turkey is different than it is for fish. It's important to make sure it's fully cooked to kill those germs.

(19:24): Finally, bacteria can multiply very quickly at air temperature. Therefore, if you're coming from the supermarket, refrigerate your food promptly. Avoid rare or raw undercooked meat, poultry or fish. Raw oysters and clams have bacteria that can progress extremely quickly in immunosuppressed individuals, and they may not give you time to get to the hospital in time to get treated. Avoid uncooked deli meats, especially during the first year after transplant, even if they're labeled as ready-to-use. We suggest you cook them or microwave them before ingesting them.

(20:08): Avoid unpasteurized dairy products such as milk or cheese. Some examples of cheeses that tend to be prepared with unpasteurized milk are Brie, Camembert, blue cheese, and queso fresco. In the United States dairy products that are produced from pasteurized dairies are labeled as such. Make sure to read the label to check whether the dairy product includes pasteurized milk from cows or goats.

(20:45): Avoid raw eggs. Some dressings or sauces, such as Caesar salad dressing and Hollandaise sauce, can contain raw egg, so make sure to avoid those.

(20:54): Always wash vegetable products even when the bags are labeled as pre-washed or ready to eat. There have been several outbreaks related to these products.

(21:14): Water safety. Avoid well water. However, if your water supply is from a well, have it tested yearly. If you must use well water, please boil the water that will be used for drinking or brushing your teeth. You can also use bottled water as a safer alternative. Listen for announcements from local officials about water safety if you have city water. And try to avoid ice, especially during travel.

(21:50): Recreational activities. Do not drink directly from lakes or rivers. In general, avoid swallowing water during swimming, and avoid swimming in areas that could be contaminated with human or animal waste like rivers, lakes or crowded public pools. Follow the signs. If there is a no swimming sign posted, there is a reason for that. That suggests that there may be a dangerous or harmful parasite in the water, for which we do not have any good treatments, or bacteria or toxic substances. If, during contact with water, an abrasion or cut occurs, clean it thoroughly with uncontaminated drinking water, and seek care.

(22:42): Let's move on to pets. Pets are wonderful and can have many emotional benefits for transplant recipients, but they can also carry a significant number of bacteria or parasites that can be harmful, particularly if your immune system is not fully working. Avoid getting a new pet the first 12 months after transplant. If you already have pets, make they're up to date on all of their vaccines. Make sure your pets visit the vet regularly and stay healthy.

(23:18): Ideally, avoid cleaning litter boxes or handling feces. If avoiding this task is not possible, maybe because of occupational exposure, like if you're a veterinarian yourself, make sure to wear gloves and masks. Avoid feeding your pets raw meat or poultry. They can get sick from this product and they're more likely to transmit it to you if they have diarrhea or vomit.

(23:49): Zoonoses are infections that are transmitted to humans through contact with animals. There are many zoonoses that we infectious disease doctors think about. In general, we suggest avoiding exotic pets, such as reptiles and amphibians because they are associated with a very high risk of getting typhoid fever or salmonella.

(24:10): Bird and bat droppings are associated with fungal infections that can go to your brain, such as cryptococcosis, or to many other organs like histoplasmosis. Rodents and rats have been associated with viruses that can cause brain infection, and there have been outbreaks that have led to death of transplant recipients. In general, anyone should avoid having contact with wild animals, such as bats or raccoons that may harbor rabies.

(24:41): Fish tanks. Cleaning fish tanks may be dangerous to transplant recipients. Anyone can get infected with a type of bacteria that is difficult to treat called mycobacterium marinum. In transplant recipients, these bacteria can go to many organs and be very difficult to treat.

(25:02): Cats and dogs have bacteria or parasites in their mouth that can be easily transmitted to humans. Always consult your doctor when a bite or an open wound occurs after contact with a pet. They might want to prescribe an antibiotic for you. Make sure to clean the area with clean water and soap before you get to the doctor.

(25:26): Moving on to environmental safety. Outdoor activities have many health benefits for transplant recipients. However, we do want you to take some precautions when doing outdoor activities including gardening and yard work. We would like you to avoid hunting or fishing, especially during the first year after transplant, or doing activities in caves or wooded areas. If you must do these activities, wear protective gear. For gardening we suggest wearing gloves and long sleeves, protective shoes, and long pants. Avoid going barefoot outside. Limit your exposure to dirt or dust. If this cannot be avoided, wear a mask.

(26:18): When planning travel after transplant, consult your transplant team about whether it is safe, and precautions you should take to reduce your risk of infection. Now let's move on to travel safety. We want you to resume as normal a life as possible, and it's possible to travel safely after transplant. It's best to plan your travel in advance. Contact your transplant team prior to travel. Make sure they agree that you are ready to resume travel. They may want you to avoid certain areas where there are current outbreaks or have a higher risk of exposure to certain infections, like malaria or tuberculosis. Also, make sure you are up to date on all your vaccines and check all vaccine requirements for your travel destinations. There may be some specific vaccine requirements that may not be safe for you, depending on what time point you are at after transplant, so you need to discuss this with your transplant team.

(27:15): Make sure to bring a summary of your medical history and a list of all your current medications with you when you travel. Bring take extra doses of all your medicines with you in case your travel plans change unexpectedly. You don't want to run out of medicine in a place where you may not have access to them. The CDC has a website where you can check all destinations and specific requirements for travel to them.

(27:46): Diarrhea. Diarrhea during travel is a very common problem for anyone, but immunosuppressed individuals can get sicker from these infections than most people. Food and water safety recommendations are even more important during travel for transplant recipients. Talk to your doctor about having an antibiotic prescription when you travel, that you can take in case you develop diarrhea.

(28:15): It's also a good idea to locate health or transplant clinics before you travel in case you develop a minor illness or you have a more severe complication that requires more expertise. Knowing where a transplant clinic is, is important.

(28:36): This is an example of the CDC website. You can put in information about where you're traveling, and it will list all the vaccines that are recommended for that specific destination, and maybe some medicines that are recommended for the specific destination as well. It will give you examples of diseases, for which you cannot be vaccinated, but for which you can adopt certain lifestyle measures to help you keep your safe. So, it may say 'avoid contaminated water and soil, avoid bug bites, et cetera', depending on what the destination is and the specific recommendations are for that area. This is very useful and anyone can access it. We as doctors always access a similar website to get current recommendations about outbreaks or travel.

(29:41): Respiratory viral infections are common after patients return to the community. Frequent handwashing, minimizing contacts, and wearing a mask are important preventive measures.  Finally, I want to discuss respiratory viral infections. Respiratory viral infections are the most common infections patients are exposed to once they return to the community. They can be prevented by frequent hand washing, either with soap and water or an alcohol-based gel hand sanitizer.

(30:03): Minimize contact with people who are coughing, sneezing, have a runny nose, red eyes, a rash or a fever. If you can't avoid contact with these people, wear a protective well-fitting high-quality mask any time you're in a crowded environment, any time you see someone with these symptoms, and any time you're visiting an emergency department or even a hospital. Usually, people that are sick visit hospitals, and these are the types of infections that you can acquire just by sitting next to someone. So keeping yourself safe is the best way to proceed.

(30:50): Finally, I want to end by saying that infections are a common complication after transplant. Even if we do everything we're supposed to do, they can still happen. Prevention works by reducing the number of infections that we'll get after transplant, and the longer time since transplant, the lower the risk. These measures to reduce the risk of infection include medicines, vaccinations and lifestyle modifications. They work, but if you're having trouble adhering to a particular recommendation, talk to your doctor. With that, I'll take any questions. Thank you.

Question and Answer Session

(31:36): [Lynne Spina]: Thank you Dr. Cuellar-Rodriguez for your excellent presentation. We'll now begin the question-and-answer session. I'm dealing with shingles and recurrences. Is the Shingrix® vaccine effective after transplant and recommended?

 (32:08): [Dr. Jennifer Cuellar-Rodriguez]: Yes. Shingrix® is a vaccine to prevent shingles, or herpes zoster, reactivation and is a very good vaccine. It is a safer vaccine than the prior shingles vaccine that used a live, debilitated virus. Shingrix s a recombinant vaccine that does not have any live virus in it. So, it's considered safe for transplant recipients and can be administered earlier on.

We used to wait until at least two years after transplant to give a shingles vaccine, but Shingrix® can be given earlier on and it's safe. How effective it is in transplant recipients is less well studied. In older adults that frequently get herpes zoster reactivation, it was very effective. But we know that transplant recipients tend to respond less well to vaccines, so they don't mount as good a response. And because this is a newer vaccine, we don't have all the information to tell you how protective this will be, but it's certainly something we recommend patients get, especially if you're already dealing with shingles.

(33:38): [Lynne Spina]: Is the use of nasal rinses and gargling a good defense against lowering the viral load of viruses and bacteria in the throat, nasal passages and thereby the lungs? Would the rinses keep you from having a more severe case of disease, cold, flu, COVID?

(34:09): [Dr. Jennifer Cuellar-Rodriguez]: I'm not sure I can say that it lowers the viral load of viruses or the bacteria load in the throat or the nasal mucosa. Certainly, it washes it out at that moment, and certainly it keeps the mucosa moist. Viruses and bacteria usually get into the respiratory tract when our mucosa is very dry and there is disruption of this mucosal barrier. So, in that sense, it can decrease the risk of getting an infection if we have moist nasal mucosa. So, it is recommended for that reason.

(35:04): [Lynne Spina]:  Does the vaccine schedule you showed also cover post-CAR T-cell therapy? If not, can you address the difference.

(35:35): [Dr. Jennifer Cuellar-Rodriguez]: So again, that chart was just an example of what may be done at your transplant center. These schedules are center-specific, so there are general recommendations, but they may be adjusted at each center. Depending on what type of CAR T-cells you receive and what lymphocytic depleting therapy they use as part of the therapy, they may or may not recommend all vaccines. It's not as well established for CAR T-cell therapy. You may benefit from some of them, but not necessarily all of them. It depends a lot on what disease and what the CAR T-cells were targeted to destroy. So having a discussion with your doctor is very important.

(36:41): [Lynne Spina]:  Do you see many infections from insect bites among immunocompromised stem cell transplant survivors?

(36:52): [Dr. Jennifer Cuellar-Rodriguez]: I live in Maryland so we don't see as many infections, but in areas that are more tropical, there are several diseases that can be severe and they're transmitted through infections. For example, malaria can be a severe presentation in transplant recipients. There are many mosquito-associated infections. One of them in the U.S. is West Nile virus. I can't say we see a lot of it but certainly it's here. And as the climate changes and the weather gets hotter in places where it wasn't as hot before, we're starting to see some of those infections from south start to show up in the U.S. So I think , over time, we're going to see more and more cases of diseases that are transmitted through mosquito bites, but certainly not a lot. However, I would still say that the recommendation is that you wear protective gear if you are able to. So long sleeves or long pants and mosquito repellent with DEET, is usually very effective in decreasing the probability of being bitten by mosquitoes and transmitting disease.

(38:42): [Lynne Spina]: After transplant, what do you recommend to protect ourselves from infection when meeting friends, attending events, et cetera? For example, should we always be wearing a mask in both the early days after transplant and later after receiving vaccines?

(39:04): [Dr. Jennifer Cuellar-Rodriguez]: That's a very good question. Like I said in my presentation, masks are one of the things that decrease the risk of getting an infection. So, early after transplant, I would recommend that if you are meeting people whom you don't know, for sure, are healthy, and the number of respiratory viruses around are high -so the flu season or COVID has started to pick up again - it's wiser to always use a mask. If you definitively do not want to get infected ,the best way to avoid it is doing by wearing a mask, but it may be uncomfortable or you don't want to do it anymore.

If you're more than two years post-transplant, you received your vaccines, you're much more protected., you're not on immune suppressants, you can still get sick from these viruses but the probability that you'll get very sick from these viruses will be lower.

So, it's all about risk reduction. There may be one meeting where there are a lot of people and you have no idea how well they are. Maybe even if you're far out from transplant, you still want to use the mask. But maybe a smaller gathering with some close friends and family, then you might want to avoid the mask. Or if it's outside, it's much safer if it's outside than inside. So, all these recommendations that we heard about COVID still apply in the sense that they are risk reduction measures. So, we're always at risk of getting an infection, any of us is, any of can get the flu, any of us can get COVID, whether you've been transplanted or not transplanted. The farther out you are from transplant, the lower the risk, assuming you're not immunosuppressed. But again, it's making good choices.

(41:21): [Lynne Spina]: At what point are transplant recipients safe to travel by plane and what is your opinion of cruises?

(41:42): [Dr. Jennifer Cuellar-Rodriguez]: So, travel by plane is a very broad question. Is it a short ride? How important is the travel? In general, we look at the entire picture and that's why having that discussion with your doctor is extremely important. You're going to be in this closed environment. Usually, the plane is not as much of a deal as the lines going into the plane. But in a crowded environment, you are significantly more at risk. So the first six months are the hardest time. We only consider you fit to handle debilitated viruses, which is not what you would acquire directly, two years after transplant. So, again, the farther out you get from transplant, the lower the risk. How important this travel is for your overall wellbeing is also something to consider.

Regarding cruises, in general, as an infectious disease doctor, I don't like them much. If there is an outbreak and you're stuck in the middle of the ocean, it can take many days before you can reach a medical clinic. But again, it's all about whether you've been looking forward to this cruise, maybe it was your 50th anniversary gift that you've been looking forward to, and if you're far out post-transplant and have gotten all your vaccines, maybe it's a good time to do it. So, it's all about reducing the risk. We can never completely avoid risk.

(43:44): [Lynne Spina]: What is the current recommendation for COVID vaccination after transplant using the bivalent vaccine? If the first injection is given at six months, when would the second one be given? How many should be given?

(44:13): [Dr. Jennifer Cuellar-Rodriguez]: The recommendations were updated on May 1, 2023, and there's an entire section on immunocompromised individuals which includes stem cell transplant recipients, CAR T-cells or cellular therapies and other immunosuppressed patients. So that is important to get.

So, if you've never been vaccinated, there are three doses. If you got one of the doses, depending on whether you got Moderna or Pfizer, it would be at least four weeks apart or three weeks if it was a Pfizer vaccine. This may vary with the different doses of the vaccines that you've received. The specific question, I think, asked about the six months bivalent, the first dose. So, assuming it was Pfizer, it would be at least eight weeks for the next dose. And if it was Moderna, I think those two would be four weeks. Again, I look it up because I can't keep track of that specifically.

And they also asked if you had received one of the non mRNA vaccines, what should they do now. In general, they're no longer recommending the monovalent vaccine at all, only the bivalent. The entire vaccination schedule should be with the bivalent vaccines. Usually, three doses are the initial recommendation. I know that they're going to have booster recommendations coming up just like we do with the flu vaccine.

(46:08): [Lynne Spina]: I am two years out of stem cell transplant for B-cell ALL. I am trying to get off tacrolimus for the third time. When I do, after a short while GVHD pops up. What percentage of patients take so long to get off tacrolimus? I was planning on having my childhood immunization at about one year, but I can't until I get off this medication. This keeps me pretty isolated due to the risk of infection. When can I get back to the world again?

(46:52): [Dr. Jennifer Cuellar-Rodriguez]: The question about the specific number of people who cannot discontinue their immune suppression because of chronic graft-versus-host disease would be better directed to transplant physician. I'm an infectious disease doctor so I don't want to give misleading information.

There may be some vaccines that you can get, even if you're still on tacrolimus. Remember, solid organ transplant recipients who get a kidney, liver or lung transplant are maintained on immune suppression for the rest of their life and that does not mean that they must be completely isolated and that no vaccines can be given. Some vaccines are safe to give starting three months or six months after transplantation. So, having that discussion and addressing those concerns with your medical team is important, what are the things that I can do right now to stop feeling this way and being so isolated?

(48:08): [Lynne Spina]: How risky is hot tub use? How risky are public hot spring resorts?

(48:23): [Dr. Jennifer Cuellar-Rodriguez]: Hot tubs have been associated with several infections starting with pseudomonas infection, and certain mycobacteria infections, which are similar to tuberculosis bacteria and are difficult to treat. So, in general they're not that safe, and we would recommend that you avoid them.

Now again, if your counts are very low, we'll say “no you cannot do this”. There's too much of a risk and this is about balancing the things you can do and the risk you take by doing them. If your blood counts are low or immunosuppression is very high, we'll likely say “no, this is a no-no”.

Over time, the risk is still going to be there, it's just that it decreases. And it depends on how well the resorts are maintained. But even in places where a lot of care is taken to maintain things and keep them clean, these bacteria stay in the tubing and they tolerate high temperatures.

So, the problem is not that they don't clean the facilities. It's just that these bacteria are hard to kill. So the risk is still there. It's all about how recently you were transplanted and how likely it is that you will acquire this infection.

So, you have to be pretty immune suppressed to get this other type of bacteria in your system and have it go to many places. If you’re not severely immunocompromised, it will likely be just a local infection. So, there will always be risk and if you were recently transplanted or if your blood counts are very low, we'll definitely say that the risk is way too high and you should not do it.

 (50:34): [Lynne Spina]: How much is risk of infection increased with GVHD?

(50:47): [Dr. Jennifer Cuellar-Rodriguez]: Significantly, and it depends on whether it's an acute episode of graft-versus-host disease, where they start you on steroids and it's controlled very quickly, versus someone who develops chronic graft-versus-host disease that is difficult to control, or graft-versus-host disease that is acute, but it does not respond to the initial immune suppression.

So, graft-versus-host disease and infections tend to happen simultaneously. However, if you have a short episode of graft-versus-host disease that responds quickly to the treatment, your risk is significantly lower than if you need several medicines to control graft-versus-host disease or to keep it at bay. If you need to be on immune suppressants for a prolonged period of time, that usually significantly increases the risk of infection over time, and some of those opportunistic infections that I mentioned during the talk can use that opportunity to cause trouble.

(52:06): [Lynne Spina]: What prevention measures can be taken against contacting mumps, measles and rubella if the vaccine cannot be given for two years post-transplant?

(52:20): [Dr. Jennifer Cuellar-Rodriguez]: Usually the recommendation is to avoid anyone who is visibly sick. That is the first thing to do. Avoid visiting places where there is a current outbreak of measles. It's important.

If, however, you live in a place where there is a current outbreak of measles, your doctors may want to test how your immune system is doing at that particular time point, even if you're not yet two years post-transplant, and decide whether the risk of giving you the vaccine is lower or higher than being exposed to so many people around you who are sick. So, the recommendation, in general, is to avoid it. However, studies have looked at if, when you are in the middle of an outbreak and your probability of coming in contact with the virus is so high that you risk getting primary measles, whether you should get the vaccine. This is not a debilitated virus. We know, at least, that the virus in the vaccine is debilitated and can be harmful, but maybe not as harmful as the primary disease.

So the way to avoid this problem is to avoid travel to places where there is a current outbreak. Obviously, avoiding anyone that has a current illness, a rash or fever, is the way to keep yourself as healthy as possible. If the outbreak is occurring where you live, then have a serious discussion with your care providers about whether you should receive the vaccine even if it's earlier than the two-year mark.

 (54:30): [Lynne Spina]:  Prior to major surgery, should someone on 10 milligrams prednisone for many years be tapered down on their prednisone to reduce risk of infection and possibly improve healing? And if so, how low should a dose be tapered?

(54:49): [Dr. Jennifer Cuellar-Rodriguez]: Someone that has been on steroids for a prolonged period of time, they're at risk of developing something that's called adrenal insufficiency. The adrenals are an organ that produces our internal steroids. So, we always produce steroids ourselves, but when we are given steroids via medicine, our system kind of shuts down and says, "well, I don't need to produce steroids because you're giving it to me". So, anyone that has been on steroids for a prolonged period of time, they need to make sure that they don't have adrenal insufficiency before stopping the steroids.

Surgery is a stress, so one of the reasons our body produces steroids is to respond to the stress. So, you need to make sure that you don't actually need the steroids for the surgery itself. Having a proper evaluation of your adrenal function before stopping it is probably as important, or more important, than reducing the risk of an infection and promoting healing.

(56:16): [Lynne Spina]:  Why do I have to get all my infant vaccines after CAR T-cell therapy?

(56:35): [Dr. Jennifer Cuellar-Rodriguez]: So, depending on the CAR T-cell product you are receiving, the lymphodepleting therapy - the chemotherapy that is given before you the get the CAR T cells - may destroy your immune system's memory about how to fight disease. If so, you'll need to be re-vaccinated to recover that ability to fight those infections.

(57:35): [Lynne Spina]: Closing. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Cuellar-Rodriguez for her very helpful remarks and thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.