Managing Infections after Transplant and CAR T-cell Therapy

Transcript of Presentation.

(00:02): [Michala O'Brien]: Introduction. Welcome to the workshop, Managing Infections After Transplant and CAR-T Cell Therapy. My name is Michala O'Brien, and I will be your moderator for this workshop.

(00:11): It's my pleasure today to introduce our speaker, Dr. Gowri Satyanarayana (aka Dr. Gowri). Dr. Gowri is the Medical Director of the Transplant and Oncology Infectious Disease Program at Northside Hospital in Atlanta, Georgia, where she diagnoses and manages infections in cancer and transplant patients. She has been the principal investigator for 11 clinical trials, examining new diagnostic methods and therapeutics for infection. Please join me in welcoming Dr. Gowri.

(00:43): [Dr. Gowri Satyanarayana]: Thank you for giving me the opportunity to speak to all of you today. As Michala said, my name is Dr. Gowri Satyanarayana, and I'm a Transplant Infectious Diseases Physician at Northside Hospital Atlanta.

(00:59): Overview of Talk. The learning objectives of my talk today include explaining how to recognize some of the common infections that happen after CAR T-cell therapy, autologous transplant (transplants using the patient’s own stem cells), and allogeneic transplant (transplants using donor stem cells), understand where these infections come from, and learn how these infections are treated.

(01:27): There are generally four categories of infections seen after transplant and CAR-T therapy. These include infections caused by bacteria, viruses, fungi, and parasites.

(01:50): This figure shows when common infections occur after transplant and what specific factors contribute to the specific infection. Not every patient will get every infection in this figure, or every infection that we talk about today

(02:16): This figure is really focused on allogeneic transplant. At the very top horizontally, there are time points after the transplant. Vertically, there are categories including immune system deficits, factors related to the transplant, the types of infections – many that we'll go over today – and then lower incidence infections that might occur.

(02:58): The first phenomenon that I want to address is a neutropenic fever, which is often the first sign of an infection in a patient who has undergone CAR-T therapy, autologous transplant, or allogeneic transplant. A neutropenic fever occurs in over 80% of patients with blood cancers.

(03:31): Neutrophils, which is where the word ‘neutropenic’ comes from, are a type of white blood cell that is killed by specific chemotherapies that patients receive.  Neutrophils help control and kill different infections. The neutrophil count decreases to zero after transplant and CAR-T therapy for several days to weeks. This is a very fragile period when patients can be very susceptible to infection. Having a fever can be the only sign of infection during this time.

(04:33): Many things can occur during a neutropenic fever. Your temperature will go over 100.4, and your neutrophil count will be less than 500, often zero. You might develop chills. You might develop something called rigors, which are shaking chills, where you feel cold to the bone. Your blood pressure might drop. You might develop confusion. You might have changes in your breathing, and you may become severely ill, requiring care in the ICU.

(05:17): Your medical team will have a protocol on how to manage and treat a neutropenic fever, but in general, the following are often done as part of the evaluation for the source of the infection causing the fever. These tests include blood cultures, where your vein is pricked and blood is obtained and sent to the lab for cultures, a urine culture, and a chest x-ray. Your team might obtain additional scans to look for infection.

(05:58): You'll be started on intravenous antibiotics, which are antibiotics given through the vein, and these are usually started within an hour of you presenting to the hospital or the clinic with a fever. Sometimes, in addition to antibiotics, antifungal medication is given in a tablet form or through the vein for the infection.

(06:26): The next category of infection is bacterial infection. This is a table that shows some common sites of bacterial infections and how we diagnose them.  

(06:47): Bacterial infections can involve a variety of sites within the body. These infections can come from outside exposure to something, but more often come from the normal bacteria living inside of you, which get disrupted by chemotherapy or other medications given at the time of your transplant or CAR-T therapy.

(07:21): Bacterial infections can be diagnosed by many different tests, but they often require cultures to identify the specific bacteria. A common cause of infection is bacteria in the blood. Bacteria can infect your intravenous catheter (IV). They can infect the lungs, which can cause pneumonia. They can infect organs, the colon, and areas in your abdomen and pelvis. They can cause urinary tract infections. They can infect the skin and even go to the brain.

(08:10): This is a table listing common bacteria that cause infection in the blood that you might encounter, and are common causes of infection in cancer patients. Your team might name some of these bacteria that might have caused an infection in your blood.  

(08:40): Generally, we like to categorize bacteria into gram-positive bacteria and gram-negative bacteria. If you are ever told that you're infected with any of these bacteria, you can understand what specific type of bacteria it is.

(09:01): Bacterial infections in the blood impact anywhere from 5% to 10% of autologous transplant patients, and 20% to 30% of allogeneic transplant patients. And there's really a wider range in patients who undergo CAR-T therapy, but these types of infections in the blood are most common by day 30 after CAR-T therapy.

(09:34): One of the most common bacterial infections that causes diarrhea in cancer patients is Clostridium difficile (C. diff.). This affects anywhere from about 8% to 13% of all transplant patients, with higher rates seen in allogeneic transplant patients. This infection usually happens in the first 100 days after transplant.

(10:07): How this infection presents is frequent diarrhea, which we usually think of as three or more loose stools in a 24-hour period, abdominal pain, and fever. Your medical team will send a sample of your stool to be tested for the bacteria, which is how the diagnosis of this infection is made.

(10:34): If any of you listening have been diagnosed with Clostridium difficile infection, you might've asked, "How did I get this?" We think several factors contribute to a patient being susceptible to this infection, including receiving chemotherapy and antibiotics in the past, and being in and out of the hospital. All these factors alter your bowel and allow the bacteria Clostridium difficile to grow and cause diarrhea. You can get this infection more than once.

(11:39): You will be given an oral antibiotic that kills the C. diff bacteria. The duration of the treatment can vary. Usually, for the first time, treatment is for 10 days, but if you have recurrent episodes, you might receive longer courses of treatment with antibiotic therapy.  

(12:09): There are some patients who have multiple recurrences of Clostridium difficile infection – and by multiple, I mean four or five times – and these patients might be evaluated for something called a fecal transplant, which is a procedure where healthy donor stool is put into your bowel. This would be a procedure that is recommended and cleared by your transplant team. Your doctor might also put you on a low-dose oral antibiotic to prevent Clostridium difficile if you have had it more than once.

(12:53): The next category of infections I will discuss is fungal infections, which occur in many cancer patients and patients who undergo CAR-T therapy and autologous or allogeneic transplant.

(13:16): Fungal infections may stem from a variety of places and are generally classified as yeast or molds. Yeast can be found in different areas – often within your own body – including the gut, the bowel, the urine, skin, nails, and outside of you as spores in the environment. Molds are most often found in the environment but also can be found under the nail beds.

(14:00): Common fungal infections that we encounter after transplants are caused by yeasts and molds. Fungal infections are infrequent in CAR-T cell recipients. The most common yeasts are called Candida, and another called Cryptococcus. And then molds, such as Aspergillus and Mucor species.

(14:46): The incidence of fungal infections is less than 2% in autologous recipients and approximately 7% in allogeneic transplant recipients. Patients can develop fungal infections due to different factors, including receiving chemotherapy – which lowers their white blood cell count for extended periods of time – being treated with steroids – which impact the way your immune system functions – and developing something called graft-versus-host disease (GVHD) after allogeneic transplant where its treatment can weaken the immune system. So overall, patients who develop fungal infections have some change in their immune system, which predisposes them to develop the fungal infection.

(15:56): Fungal infections are managed in a few ways. Transplant and CAR-T recipients are placed on preventive antifungal medicine to help prevent fungal infections. Despite this, patients can still develop fungal infections. Sometimes it's after the preventive medicine has been stopped, other times it's even while taking the preventive medicine, because you can develop a fungal infection that is resistant to the preventive medication you've been prescribed.

(16:49): If you do develop an active fungal infection, it is treated with an antifungal, which is often given in a tablet or through an IV. Some fungal infections can infect the sinus, the lungs, or the skin, or other tissue sites, which may require surgery. And again, this would need to be a treatment recommended and managed by your transplant or CAR T team.

(17:28): The next category of infections is viral infections. Similarly to fungal infections, some types of viral infections come from within you, while others are spread via contact with other people, usually through respiratory droplets or contaminated stool.

(17:58): The first group of viral infections is called herpes simplex and varicella zoster. Varicella zoster is also known as shingles. These are common viral infections that can occur after transplant and CAR-T therapy. Herpes simplex and varicella zoster viruses are viruses that are dormant within a patient. This means that the patient was exposed to the infection at some time in the past, and due to changes in the immune system after transplant and CAR T-cell therapy, the infection comes back.

(18:52): These viruses often cause an infection that looks like small blisters filled with fluid. They can cause an infection on the skin, genital area, lips, inside of the mouth, or even infect the brain. A lot of patients describe these lesions as painful.

(19:22): These infections are treated with an antiviral medication. Some medications are available as tablets, and others are only available through the intravenous route. Most transplant and CAR-T programs will place a patient on medication to prevent these infections. However, patients can still develop herpes simplex and varicella zoster infections despite being on these medications, especially if doses of these preventive medications are missed.

(20:10): The next category of viral infection is called cytomegalovirus (CMV). This is another viral infection that patients can be exposed to before transplant or CAR T-cell therapy that can reactivate, or grow inside of you, after transplant or CAR-T. CMV is quite rare after autologous transplant.

(20:54): Symptoms of CMV infection can be quite variable, and include fever, vomiting, diarrhea, cough, vision changes, and abnormal lab work which your transplant and CAR-T team will be assessing. The diagnosis is made by a blood test for the virus, which all transplant and CAR-T programs should have access to. Interestingly, this virus can also affect organs like the colon, and a biopsy of the tissue can show the virus.

(21:43): Treatment for cytomegalovirus infection involves either a tablet or intravenous antiviral medication. This type of viral infection is most common after an allogeneic transplant, and most transplant centers may place the patient on a preventive antiviral medication.  

(22:40): Respiratory viral infections, other than COVID, are quite common after transplant or CAR-T. The challenge is that very few of the respiratory viruses that we find in our diagnostic testing have an effective treatment.

(23:07): If your medical team suspects that you might have a respiratory viral infection, they will usually try to make the diagnosis by swabbing the nasopharynx.  A swab is placed inside your nose and goes down the back of your throat. The swab is sent for what's called a polymerase chain reaction (PCR) test. Or you might have a procedure where they sample fluid from the lungs, and that fluid is also sent for a PCR test.

(23:48): Some of the most common viral infections that we see that impact the lungs are influenza, or flu, respiratory syncytial virus (RSV), parainfluenza, and human metapneumovirus. Currently, only influenza has an approved antiviral medication for treatment. The other viral infections do not have any specific approved treatments. Your transplant center might have very individualized approaches to some of these infections, which might involve giving you medications to support you while getting over this infection.

(24:47): The last viral infection I will mention is called norovirus. This is a viral infection that infects the gastrointestinal tract and can cause diarrhea, nausea, and vomiting. This is often known as the ‘cruise ship virus’. Unfortunately, this infection has gone beyond cruise ships and affects our transplant and CAR-T patients.

(25:22): This infection can be acquired in the community or the hospital, and it can lead to chronic diarrhea, most often in allogeneic transplant patients. And when I mean chronic diarrhea, I mean diarrhea that can keep going for beyond two or three weeks. Unfortunately, at this time, there's no proven treatment for norovirus infection, and your medical team will manage your symptoms with other medications.

(26:09): The last category of infections I'd like to discuss is parasitic infections, and there's one main parasite patients should know about, which is called Toxoplasma. This is another infection that patients can be exposed to before transplant, and it can remain dormant –or quiet -- within the body until after transplant, when it can cause an infection in the blood, lungs, or brain.

(26:49): Generally, the Toxoplasma is ingested and can be transmitted through undercooked or contaminated meat, contact with contaminated soil, and coming into contact with contaminated cat feces. This is often why, for those of you who have pet cats, your transplant or CAR-T medical team might recommend that you no longer handle cat litter. Handling cat feces, not washing your hands thoroughly, and ingesting the parasites from your own hands are all common ways this infection is transmitted.

(27:55): The symptoms of this infection can involve different areas of the body, and therefore, the first sign is often actually fever. Patients can also develop headaches or changes in the way they think. The diagnosis for this infection can be done via a blood test for the parasite, a spinal fluid test if your team is concerned that it's infecting the brain, and rarely, a brain biopsy.

(28:35): The treatment for Toxoplasma infection is via either tablet or an intravenous set of medications, and the treatment can be for six months or longer. I would like to note that most allogeneic transplant recipients are screened for this infection, meaning your transplant team will do blood work to see if you have evidence of being exposed to this infection before your transplant. If there is evidence that you've been exposed to this infection, you will be placed on a preventive medication after the transplant so that this infection does not recur.

(29:38): Infection prevention is important, and there are specific ways patients and caregivers can protect themselves. I would like to preface this by saying that you will receive specific guidance from your transplant and CAR-T team. However, the majority of centers will recommend hand washing, because strict hand hygiene is very much the ‘bread and butter’ of infection prevention. Patient and caregiver masking and vaccinations are also recommended. No gardening, and limiting exposure to soil and dust for at least six to 12 months, is important because there are many organisms that you can be exposed to and lead to infection after CAR-T or transplant, residing in the dust and soil. Also, as I mentioned, no handling of cat litter, and avoid drinking well water. Your immune system is not normal after CAR-T or transplant, so it is important to keep this in mind.  

(30:59): For those patients who want to travel outside of the US, it will generally need to be approved by your individual care team. Many factors go into patients being approved to travel abroad, which can be a bit more complex depending on any complications you might have after CAR-T or transplant.

(31:28): Vaccinations are given after transplant and CAR-T, and there are general guidelines and schedules for getting specific vaccines at specific time points after these treatments. The vaccine schedule is often individualized, meaning it's adjusted for each patient based on whether you are receiving additional chemotherapy after transplant or CAR-T, and also if you have graft-versus-host disease after an allogeneic transplant.

(32:19): Every center has its own diagram, and your medical team will go over when the vaccinations start, and which ones are due. Often, the first set of vaccines are recommended as early as three months after your CAR-T or autologous transplant and six months after your allogeneic transplant.

(32:54): Conclusion. To summarize, what I have discussed today, many different infections can occur after CAR-T therapy, autologous transplant, and allogeneic transplant. For many of the common infections that occur in our patients, we give our patients preventive medications – which we call prophylaxis – to try to prevent infections. Your education and knowledge about specific infections and their treatment will help you if you develop one after your transplant or CAR-T-cell therapy.  

Question and Answer.

(34:00): [Michala O'Brien]: Thank you, Dr. Gowri, for this informative presentation. We'll now move into some questions.  

(34:18): Our first question is from somebody who keeps getting a cold. This has been happening for a year, and nobody is sure what they can do about this. Do you have some advice?

(34:31): [Dr. Gowri Satyanarayana]:  Sure. We do see a few patients like this each year. First and foremost, I hope you have seen an infectious disease physician, because sometimes they might take another approach to solve the problem you're experiencing.

(35:11): What type of cold is it? Has it been diagnosed? Was it a virus? Is this more a form of pneumonia due to a bacteria? Is it always the same thing? And then, is there anything about your immune system that is not quite normal, that is predisposing you to have this recurrent cold?

(35:37): The other comment I would make is that there is also another specialty group of doctors, called Immunologists, that will assess your immune system in more detail to see if there is anything abnormal with your immune system that may be predisposing you to have something like a recurrent cold. And lastly, I would also say that it is important to make sure it is a recurrent cold, and that it isn't an alternate diagnosis or another condition that's being missed.

(36:21): [Michala O'Brien]: What are your thoughts about when it's okay to be around pets after CAR-T therapy or transplant?

(36:29): [Dr. Gowri Satyanarayana]:  So again, this guidance might vary from program to program. However, I think most medical providers and the transplant teams would consider dogs to be the safest pets. And generally, after the first 100 days is often a good time point to know how well the transplant is working. If you’ve gotten an allogeneic transplant, do you have any graft-versus-host disease? Is it safe for you to be around your pets?

(37:26): In general, I think cats and cat litter are going to be the pet category that's generally not recommended across the board for most patients.

(37:44): And then other pets – like birds and lizards – are likely not going to be recommended as well. Reptiles might have harmful organisms on their skin. Bird poop carries something you could inhale and then develop infections.

(38:10): For CAR-T and autologous transplant patients, the day 30 mark is often a time point where many assessments are done, when you will likely to get clearance from your CAR-T or transplant team, and it's okay for you to do certain activities like revisiting your pets, etc.

(38:43): [Michala O'Brien]: This is a question regarding the probiotic, Florastor, which contains the yeast, saccharomyces boulardii. Do you have any strategy to prevent the recurrence of C. diff?

(38:55): [Dr. Gowri Satyanarayana]: This is a really great question. There are some transplant programs and CAR-T programs that recommend that their patients do not use probiotics.  And part of the reason is that there have been some reports of patients developing infections from the organisms in the probiotic, and therefore, the transplant or CAR-T centers do not want to put their patients at risk of developing infections from the probiotic.

(39:40): I would first discuss with your transplant or CAR-T medical team what their recommendation is. In the general population of those who have not undergone transplant, CAR-T or chemotherapy treatment, there is data that suggest probiotics help prevent recurrent C. diff. Part of this is that patients need an improved immune system in order to get over and clear C. diff. The other part is also minimizing your exposure to antibiotics, which can re-deplete your healthy gut bacteria.

(40:34): Some other things that I would mention that you should discuss with your transplant or CAR-T medical team are eating cultured yogurt or drinking drinks such as kombucha, or kefir. These have live cultures. Also eating sauerkraut, which has good bacteria in it. But I would definitely discuss all of those with your medical team to make sure that you're following the guidance that they recommend for their patients.

(41:18): [Michala O'Brien]: What treatments have shown the most improvement? After two and a half years, this patient is still having urinary tract infections.

(41:28): [Dr. Gowri Satyanarayana]: This is one of the more common issues patients face after transplant and CAR-T therapy. For you as well, I would recommend seeing an infectious diseases physician. You may or may not have also seen a urologist, because it does take a bit of a multidisciplinary team to address recurrent UTIs.

(42:03): The first step in assessing recurrent UTIs is to ask if it is the same bacteria each time, or if different bacteria are causing the UTI each time? Are there any issues anatomically or with the urinary system that are predisposing you to developing recurrent urinary tract infections? These could be things like kidney stones, strictures, something called reflux, or incomplete bladder emptying. There could be different underlying issues that predispose patients to recurrent urinary tract infections, and that's where a urologist can help with the evaluation.

(43:04): The other part is that if it is the same bacteria causing the urinary tract infection each time, have you received a long enough course of treatment to treat the urinary tract infection? Sometimes, two weeks of antibiotic treatment is not enough, and you need a longer treatment course.

(43:29): If all of that has been done and nothing has been found, there are cases where patients will be placed anywhere from three to six months on an oral antibiotic to try and see if the urinary tract infection can be prevented. However, for this patient, I would definitely recommend that you have an infectious diseases evaluation and a urologic evaluation if you have not already done so.

(44:05): [Michala O'Brien]: Can you discuss some ways to diminish respiratory viruses, especially for people who have lung graft-versus-host disease (GVHD)? Are there some resources to help evaluate risks and what activities they can do?  

(44:20): [Dr. Gowri Satyanarayana]: Respiratory viruses for patients who have lung GVHD is a really big area of interest within research. I don't think we really know and understand all the factors that go into how viruses impact the lung function, how much, and how well patients recover.

(45:02): There are ways that patients can prevent and protect themselves. Most transplant programs will recommend vaccination for influenza and COVID. The RSV recommendations have not been finalized yet by our national society, but there will be recommendations for those vaccines for our transplant and CAR-T patient.

(45:41): If a patient is not a candidate for those vaccines, the medical team will recommend that your caregivers and those close to you be vaccinated. Transplant programs will also recommend masking and hand washing. In the peak of these seasons when a lot of these viruses are circulating, it will be recommended that they limit how much they're going out into crowds or being around large groups, to limit exposure.

(46:24): From an immune system standpoint, for respiratory viruses, unfortunately, if you have graft-versus-host disease, you need the treatment and medications to control the GVHD. Adjusting or lowering the dosages of your immune suppression medication, may not be possible. One strategy some transplant centers utilize is something called the immunoglobulin level – or IgG – and give replacement if the IgG level drops. Those are some of the ways that I have seen different centers recommend prevention for respiratory viruses for patients who have GVHD.

(47:22): [Michala O'Brien]: Can you speak about managing the risk of measles, especially for those who have not yet been vaccinated post-transplant?

(47:32): [Dr. Gowri Satyanarayana]:  This is a great question, and a very hot topic right now, given the spread of measles in certain states in the US. The issue with the measles vaccine for our CAR-T and transplant patients is that the measles vaccine is a ‘live-virus vaccine.’ That means there is live virus material in the actual vaccine. If you receive the vaccine and your immune system is not recovered, or still suppressed, you could actually develop an infection from the vaccine. At this time, for allogeneic transplant patients, the recommendation for the measles vaccine – which is the measles, mumps, and rubella (MMR) vaccine – is two years after transplant.

(48:45): Even two years after transplant, if patients have significant graft-versus-host disease and are on immune suppression, the measles vaccine is still not recommended. If you've received CAR T-cell therapy or autologous transplant, and you're still receiving any type of chemotherapy, you're not a candidate for the measles vaccine.

(49:10): What do patients do? Well, the recommendations at this time are for caregivers and close contacts, to be vaccinated, and avoid going to areas where the rates are quite high. If a transplant or CAR-T patient is suspected of having measles, there will be specific protocols followed by your medical team.

(49:46): Unfortunately, at this time, yes, you are correct; because most of our patients are not candidates for the live-virus vaccine, we are left kind of mitigating this infection with those around our patients.

(50:06): [Michala O'Brien]: What's an effective treatment for toenail fungus after CAR-T therapy if there are liver issues?

(50:13): [Dr. Gowri Satyanarayana]: This can be a challenge because many of the medications used for toenail fungus – which are oral tablets – are metabolized through the liver. So first, I would recommend that we culture and identify the exact strain of the toenail fungus you have. Then, we can look at what antifungals might kill this strain, and whether any are less toxic to the liver.

(50:54): If all of the medications are off the table, one route might be to see a podiatrist – a doctor who specializes in feet and toenails. They can see if you are a candidate for any type of toenail removal or cutting down the toenail in any way. Sometimes the podiatrist can also be helpful in getting toenail specimens for culturing, so that we can identify the exact toenail fungus that we could target with an antifungal medication.

(51:39): There are also topical medications available for toenail fungus, but my sense is you've probably already tried those, and they haven't helped.

(52:02): [Michala O'Brien]: Six months after a CAR-T therapy, this patient got a salmonella infection requiring hospitalization. How did that infection happen?

(52:12): [Dr. Gowri Satyanarayana]: Even non-transplant or non-CAR-T patients do get salmonella. And we think most likely, you contracted this infection from eating something that might've been undercooked or contaminated with salmonella.

(52:34): Often, we think about eggs, or things that come from poultry, that are contaminated with salmonella. We ingest them, and the bacteria can cause diarrhea. It can also go into the blood, and that infection is treated with antibiotics. So most likely, you were exposed to salmonella through something you ate.

(53:06): [Michala O'Brien]: This person has water from a well in their home. Are there any options for her?

(53:14): [Dr. Gowri Satyanarayana]: Yes. So, the issue with well water is that some organisms can grow and be present in well water. So many patients who have undergone CAR-T therapy or transplant and only have well water, purchase or install some type of filtration system. That might be the general recommendation from most transplant care teams.

(53:47): [Michala O'Brien]: Do you recommend wearing a mask when somebody is on immunosuppressants three years after a transplant? They also had pneumonia last year.

(53:58): [Dr. Gowri Satyanarayana]:  Yes. I think most transplant centers would recommend continuing to mask while you are out in public.

(54:10): [Michala O'Brien]: Do you think IVIG is beneficial, and is it also possible to get MMR antibodies from IVIG?

(54:24): [Dr. Gowri Satyanarayana]:  Great question. I think the general community does believe and use IVIG in our patients, especially when levels drop to less than 200, or if you have had recurrent infections, then less than 400.

(54:58): Now, you might get MMR antibodies through IVIG, but the question would be, how effective are those antibodies, and are there enough to really form a protective response? I think at this point, the transplant community thinks there is not enough to protect a patient against measles, because I'm not sure it's possible to quantify the amount of measles antibodies that you would be getting from each IVIG infusion. It could vary, so there might be issues upon relying on IVIG for protection against anything related to measles, mumps, or rubella.

(56:02): [Michala O'Brien]: Closing. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Gowri for her helpful remarks today, and thank you to the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way.