Dr. Mariam Hanna:

I'm Dr. Mariam Hanna, and this is The Allergist, A show that separates myth from medicine, deciphering allergies and understanding the immune system.

So in 20 years from now, I'm going to have a lot of stories to tell, but one of them that I'm going to tell to the next generation is probably when COVID-19 was declared a global pandemic, and the borders closed, children's activities were canceled, stores closed, and yes, even schools closed. We braced ourselves and many, many, many graphs and projections later, it was over, and it was an overall rather quiet series of months from the pediatric illnesses' standpoint where really we saw a huge decline in the number of runny noses, not too many colds, not too many respiratory illnesses, we distanced, we had masked up and I guess less stuff spread. The brake pedal technique, as we all called it, had helped slow things down and eventually things went back to normal. Gradually. While some may have liked for there to be a new normal, most just went back to what they had before and we all got a pseudo immunology degree over that year and a half we became resident immunologists.

So fast-forward to my clinic, along comes this lovely, cute guy, really long eyelashes, he's four, he's got a perpetual runny nose, multiple respiratory infections, they say, a few rounds of antibiotics, tough for them to remember if it was his ears or maybe it was his chest. He's got a fever and it would seem that that happens every other month. He just started daycare last year and he's missed too many days for them to count. These frustrated families demand an allergist consult, because they're frankly just fed up and they need to know if this is allergy. But really, honestly, the scarier question for them, the unasked question that lingers in my room is, is his immune system okay? Well today's episode is an exciting one. We're going to get into the heart of our specialty and delve right into immunology, an area that is always daunting and to think about it, it's actually incredibly intriguing to discuss.

So I am especially excited to introduce today's allergist, or I should say immunologist, Dr. Rae Brager. Dr. Rae Brager is a pediatric immunologist and allergist at McMaster Children's Hospital. She's an associate professor of pediatrics at McMaster. She's also a community pediatric allergist in Toronto and has a special interest in advocacy for patients with special needs, in particular, autism. She received her medical doctorate at Queen University and trained in pediatrics, immunology and allergy and stem cell transplantation at SickKids in Toronto. Dr. Brager, thank you so much for taking time out of your busy schedule to join us and welcome to the podcast.

Dr. Rae Brager:

Thank you. Thanks for having me.

Dr. Mariam Hanna:

All right. Dr. Brager, as you can tell, I'm pretty excited, a little bit worried, a little bit nervous that we're going to go into immunology, but let's do it. So let's start. What is immunodeficiency?

Dr. Rae Brager:

That's a great question. The answer is there are many answers to that question, but in general when we think about defects in the way our immune system works, we think about difficulty fighting infections, and we can also think about dysregulation or lack of regulation in the immune system. So if you think about your immune system as a number of different subsystems that have to work together to protect us from infections and protect us from autoimmunity, when our own immune system attacks our body's systems and organs, then all of those pieces of the same puzzle have to be set up in the right configuration in order for it to function. So deficiency in any of the aspects of the immune system can then lead us to be vulnerable to infections, make it more difficult for us to recover from them, and also to have our immune systems be overactive and cause problems in that regard.

Dr. Mariam Hanna:

Too low, overactive and leaving us vulnerable. So the warning signs or the red flags that we see for immunodeficiency get a little bit complicated in that the normal child gets eight to 10 colds a year, and some of that snot gets sucked back into their ears, some goes into their chest, some have undiagnosed asthma like this at the very general pediatric sense gives us a challenge I think in primary care and in subspecialty care. When the kids get so many colds, and some of them are febrile, not every time do they get an X-ray with their pneumonia, how do you know when this is a flag and when this is not? And perhaps that's the better way of getting to this one.

Dr. Rae Brager:

That's a great question. I would even top up your eight to 10 infections a year to 10 to 12 is my sort of normal range, which really means that kids in the preschool and school age should be getting sick about once a month and that's normal as long as they're bouncing back and as long as they're not requiring hospital admission, intravenous antibiotics or lots of intervention, and as long as they're recovering in the meantime, they can still have a runny nose all the way through, that's allowed.

Dr. Mariam Hanna:

Okay, great. So then do you think that the last bit of them are the scarier ones or the ones that you put more weight on?

Dr. Rae Brager:

Definitely more worrisome. So there are things like recurrent or deep-seated abscesses like abscesses in the skin or in the organs. Also persistent thrush in the mouth or fungal infections in the skin or nails. This is outside of the newborn period where some babies can typically have thrush in their mouths. A need for intravenous antibiotics to clear infections is another one of those flags. And then more than two or I would say more than one if it's really devastating, serious deep-seated infections like septicemia, bacteremia, meningitis, and a family history of immune disorders is the last one. So that always definitely flags for us as something that's a bigger warning sign. When we pull it all together, it is a very contextual level of worry, and it's I think very difficult for an immune deficiency expert to be able to give a gestalt to pediatrician or a family physician because it really does have a smell to it. When we see a patient who's worrisome in the clinic and about whom we're so concerned that we want to investigate immediately.

Dr. Mariam Hanna:

I think looking back, when I think about my pediatrics residency and some of the patients that were admitted and were super sick and required IV antibiotics, come to think of it, they didn't all get an immunodeficiency workup. Is that a failing in the system or we're not thinking about it soon enough or are we missing all these guys?

Dr. Rae Brager:

I think there are a couple of ways to look at that. We think that probably most kids who have bad infections are probably just unlucky or they may have something different about their immune function that's temporary. Maybe they had a preceding infection that made them more vulnerable. Maybe they were exposed to a particularly virulent strain of whatever infection they had. But I do think there's a cultural issue in medicine in that immunology is not top of mind for many practitioners. It's not taught much or well in medical school and certainly not in the clinical part of training. So if you're not pursuing it might be something that is less familiar and not really on people's radar in terms of what to consider. I find myself often being the last of a string of consultants when people really don't know what's going on. And I'm the first pediatric immunologist to have started working at my hospital, which is a tertiary care children's center in a big city that has a large catchment. And the patients who are new to my practice just weren't really seen unless they had a very obvious immune deficiency. And the population of our clinics has probably quintupled in the last few years.

Dr. Mariam Hanna:

They often associate our specialty with the zebra. I think the immunologists are the ones that bring the zebra into our specialty. You guys are the zebra stripe earners out of this. I want to ask you about routine screenings. So are there immunodeficiencies that are part of our routine screening? And if so, which ones or mind one?

Dr. Rae Brager:

So screening can be looked at in different ways. So in Ontario, where I practice in many provinces, but not all provinces in Canada, there is newborn screening for severe combined immune deficiency, which is typically part of newborn screening for many disorders like metabolic issues, cystic fibrosis, sickle cell disease and other things. So newborn screening helps us to identify most cases of severe combined immune deficiency. Beyond that screening would have to be done by a provider, so a family doctor, a pediatrician or a clinical allergist, an immunologist, would have to undertake screening. And probably the test that I see done the most in that regard is looking for immunoglobulin levels.

Dr. Mariam Hanna:

So this landscape has changed so much and so dramatically actually in the past 10 years. New therapies, new interventions, new ways of testing. I tell you, immunology is scary even from my undergrad years and I did immunology in my undergrad years. However, so much has changed. On the front lines, what do you think are kind of big key changes that have happened over this past decade?

Dr. Rae Brager:

So newborn screening that I was referring to just now is a huge game changer in my practice. When I was in training, kids who had severe immune deficiencies would have to get sick before they would be able to be identified, and they would be very, very sick. Even with all the supportive measures we could offer them, they would often be in intensive care units and requiring massive interventions. And those patients had less good outcomes even when we used definitive treatments like stem cell transplantation because they were so sick going into transplant. Now with newborn screening, we're able to identify kids while they're still really well and they often have transplants much sooner and they're healthier going into transplant. So the morbidity and mortality associated with the procedure is much, much lower and the outcomes are much better. But for some of the severe combined immune deficiencies, we now have gene therapy, which circumvents the need for a lot of the toxicities that were previously associated with stem cell transplantation. So it's been a huge change for how patients are managed and what the experience is like for families.

Dr. Mariam Hanna:

That's incredible. Speaking on gene therapy, we also see advanced therapies in other specialties, specifically cancer research. What do we see there with acquired immunodeficiencies post-cancer interventions?

Dr. Rae Brager:

There is a huge focus on the role of the immune system in the development of cancer and in treating cancer. And I just would like to take this moment to be a bit smug about how the immune system is really the issue in many disorders, although it is not acknowledged as such, it's really all about the immune system. So there are some brilliant minds who have been harnessing the power of the immune system to treat cancers with targeted therapies like chimeric antigen receptor T-cells, which are the patient's own engineered cells, which can then fight tumor cells in disease like lymphoma and leukemia. But because we're manipulating the immune cells in the process, sometimes that can actually cause immune deficiency in patients who have had this therapy, and in that situation we have to supplement their immune function in the backend

Dr. Mariam Hanna:

And is that permanently supplement them or temporarily supplement them? Did you get rid of one disease and win another?

Dr. Rae Brager:

It probably is treating one set of problems for another, but I will say it's a much less lousy set of problems that you end up with in this scenario. But the therapy is new enough that we don't really know the answer. Interestingly, CAR T-cell therapy was initiated first in children, which is very unusual in medicine where almost everything is researched in adults first. So the first CAR T infusion was done, I believe 11 years ago by our colleagues at the children's hospital in Philadelphia. And that patient is doing well who received the first CAR Ts, but we're learning more about the process all the time. So my presumption is that in patients in whom their CAR T-cells persist that they probably will continue to have low B cell counts and they won't be able to make their own antibody probably for life, but we might get a lot smarter in the next 10 years and be able to learn how to fix that problem.

Dr. Mariam Hanna:

Already talking about gene therapy and CAR T-cell therapy is pretty insane that it's actually happening at a clinical level when we were talking about it theoretically in our textbooks as we were training. So the fact that this is even being applied in this generation is already incredible. So I clearly heard Dr. Brager here on the show say that the immune system is responsible for much of the diseases in our entire body. So we're going to get to some serious myth busting, and I think this needs to happen with this topic, because immunology, everybody, as I told you over the past pandemic, became a resident immunologist with expertise on the topic. So I think we need to bust some serious myths here. So let's start with what is not immunodeficiency? Tell me that.

Dr. Rae Brager:

So kids who go to daycare and school who get a cold and get better for a few days and then get another cold and then get better for another few days and then get another cold, that is not immune deficiency. Kids who have a cough that lasts for months after they have a cold, that's not immune deficiency, but probably see your pediatrician, family doctor or friendly neighborhood allergists to think about whether you have asthma, and people who have chronic fatigue with no infectious symptoms or autoimmune systems, that's probably not immune deficiency. And people who have recurrent vaginal thrush, that's probably not immune deficiency. People who have recurrent bacterial urinary tract infections, not immune deficiency. So there are lots of things that aren't, in fact, most of the patients that I see with referrals for is this immune deficiency don't have one that I can identify and aren't the kind of patient that I would suspect have one, which is okay, we like to-

Dr. Mariam Hanna:

Yeah, why don't we have the top 10 not immunodeficiency list? I think that needs to be made just as quickly as the top 10 red flags of immunodeficiency. I think, I don't know.

Dr. Rae Brager:

I think that's a great idea.

Dr. Mariam Hanna:

So in the post lockdown COVID era, it seemed like kids got sicker. Is that immunologically possible? Kids got sicker, their immune systems weren't primed the same or something? Did that happen?

Dr. Rae Brager:

The real answer is we don't exactly know what happened and we can't study it very well because we don't have anything to compare it against. This is such a unique singular experience in which patients and humans had an isolated period, which really has never happened for such a prolonged time in history that we know of. So I think it's so unique that anybody who thinks they know the answer is not a scientist. So that's my first caveat, but I have some suspicions about some things that might have played a role. And I just want to say that the media approach to this topic has really been a bit disturbing to me as a physician and especially as an expert in immunology because it's very presumptive and tossing around terminology like immunity debt really doesn't make any sense at all. So I just want to put that upfront.

But overall, I think there are a few things that happened. One is that we got really attuned to symptoms. So when we were worried about COVID infections, we paid a lot of mental attention to how we felt and how our kids felt and we were watching for the first sign of any infection and it became something so magnified in our minds that we're very alert to it now. And even still this long into COVID being part of our endemic lives, I see people really spending a lot of mental energy on how many symptoms they have and their kids have, things that we really would not have paid attention to in the past. So that's probably a big one. And then also we had a cohort of kids who were never exposed to a lot of the childhood infections, and then all of a sudden got exposed all at once. So it seemed like everybody was terribly unwell all at the same time. And we had some particularly virulent strains of normal respiratory childhood viruses. And we also had a lot of skepticism about the medical field, about vaccines, not only COVID vaccines, but also influenza vaccines and regular childhood vaccines, because everyone's lay expertise seemed to blossom, but some more in a conspiracy theory direction than in a medical science direction.

And I think all of those things put together probably added up to everyone seeming a lot sicker for the last year after lockdowns were finally ended.

Dr. Mariam Hanna:

I won't even paraphrase what you said, that just needs a pause and another question. All right, one more. Is there any point in cord blood banking? You're talking about advanced therapies, gene therapies, all these like Car T-cell, if I bank my baby's cord blood, is there any utility to that?

Dr. Rae Brager:

Oh, this is a great question. I love this question and I love to get on this soapbox. So court blood banking is something that was popularized I think even before my kids were born, and their teenagers now, as a theoretical useful tactic for parents. But really it's, in my opinion, mostly a corporate scam. And the reason I say that is that most of the uses for stem cells that we have now can be executed using stem cells that you can harvest from the person's own body. So children, for example, who need stem cell transplants from their own stem cells. Kids who have solid tumors require this sometimes to be able to receive more expedited cycles of chemotherapy so those patients can have their own stem cells harvested. It's not of any benefit really to have one dose of stem cells in the bank, and patients whose siblings could be stem cell donors for them, their siblings stem cells can be harvested. It's actually getting easier to do that with less intervention and less invasive procedures.

So for now, we don't have really a use for your own or your siblings cord blood that's banked. Anybody who could be a donor if they're living could be a donor at any time. And the thing that I think is important to remember is that these companies really prey on vulnerable parents who really just want the best for their kids. But the thing I would encourage very deeply is for people to consider donating their baby's cord blood, because although it probably won't be useful for your particular baby, it might be lifesaving for someone else's baby. So if you live in a place where there's public cord blood banking like Alberta and Ontario and possibly some other provinces that I'm just not as up on, it's definitely worth looking into whether you can do that. It's a very generous thing that you can do with your baby's cord blood that otherwise will go in the garbage.

Dr. Mariam Hanna:

Myth busted, money saved, and an opportunity to save someone else's life. Our card carrying immunologist has been fascinating today. So we are going to wrap up today's episode with three key messages that Dr. Brager would like to impart on patients and/or physicians on today's topic, immunodeficiency, Dr. Brager, over to you.

Dr. Rae Brager:

My first takeaway is something I say to my families that I look after in my clinic all the time, which is that the immune system is much smarter than us. I am far from the smartest immunologist, but even the very most brilliant minds among us is completely overshadowed by the complexity of our immune system. So forgive us when we can't say definitively what is wrong with your immune system. So that's number one. Number two is, and this is a bit of a reiteration of something we already talked about, but most concerns about the immune system that I see referred to me end up not being immune deficiency. And that's a good thing. So I think people should remember that although your brain really wants an answer for why things are the way they are in your life or your child's life, the best answer is that there's nothing wrong with you.

That is a good answer, even if it's unsatisfying, because it doesn't untangle all the messes that you've been facing in your life. And the last thing that I would say is that I think that many of us have gone through a process of what I call risk distortion over the last few years during the pandemic and subsequently where we're afraid of a lot of things that we weren't scared of before. I see this in my patients who have immune deficiencies, and I also see this in my healthy patients that we're really afraid of getting sick. And the thing that's so great about immune systems is that they're really good at learning. So every time that your child has an illness or you go through another cold and it feels like the millionth one you've had, it's an opportunity for yourselves to get smarter. So if you try to think about it that way, sometimes it makes it a little easier to get through.

Dr. Mariam Hanna:

Thank you Dr. Brager for joining us on today's episode of The Allergist. I think we have learned a lot about immune deficiency and it has been essential to get this podcast series going, so we hope to chat again soon and dig further into some immunodeficiency and bust some more myths. That was my favorite part.

Dr. Rae Brager:

Thanks so much for having me.

Dr. Mariam Hanna:

This podcast is produced by the Canadian Society of Allergy and Clinical Immunologist. The Allergist is produced for CSACI by PodCraft Productions. The views expressed by our guests are theirs alone and do not necessarily reflect the views of the Canadian society. This podcast is not intended to provide any individual medical advice to our listeners. Please visit www.csaci for show notes and any pertinent links from today's conversation. The Find an Allergist app on the website is a useful tool to locate an allergist in your area. If you like the show, please give us a five star rating and leave a comment wherever you download your podcasts, and share it with your networks and your neighborhood immunologist. Thank you for listening. Sincerely, The Allergist.