Studying the Impact of Precision Medicine in Pediatric Critical Care with Dr. Joseph Carcillo

Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure Renewal | Grantome NIH Funding Information

About Research | University of Pittsburgh Department of Critical Care Medicine

Precision Medicine | The U.S. Food and Drug Administration

Precision health: Improving health for each of us and all of us | The Centers for Disease Control and Prevention

The Promise of Precision Medicine | The National Institutes of Health

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Voiceover: This podcast is for informational and educational purposes only. It is not medical care or advice. Clinicians should rely on their own medical judgements when advising their patients. Patients in need of medical care should consult their personal care provider. Welcome to "That's Pediatrics", where we sit down with physicians, scientists, and experts to discuss the latest discoveries and innovations in pediatric healthcare.

Dr. Amanda Poholek: Welcome to That's Pediatrics. I'm your co-host, Amanda Poholek.

Dr. Arvind Srinath: And I'm your co-host, Arvind Srinath.

Dr. Poholek: Today, we have Dr. Carcillo with us for our podcast. Dr. Carillo is a professor of critical care medicine and pediatrics at the University of Pittsburgh, and a physician scientist in critical care medicine at UPMC Children's Hospital. His research expertise is in the area of septic shock and multiple organ failure in children. Thank you so much for joining us today, Dr. Carcillo.

Dr. Joseph Carcillo: Oh, thank you for having me.

Dr. Poholek: So, I was hoping you could get us started by just giving us some background in sort of how you got interested in the field of septic shock and multi-organ failure in children.

Dr. Carcillo: Sure, well, that started over 30 years ago. When I first started off in the 1980s, if you had an infection, people didn't know quite what to do. And if the infection overwhelmed your body, they certainly didn't know what to do. So the children would come to the hospital in extremis, and I thought over my career would be a disease that when I was a child had a 98% mortality. My goal was to see if, with research, if we could drive it down to less than 10%. So that's why I chose it as a research interest and goal.

Dr. Poholek: Yeah, that's a lofty goal.

Dr. Carcillo: Yeah, well I figured 30 years, right? So you don't have to do it over a couple years.

Dr. Poholek: Amazing.

Dr. Carcillo: And we've been successful. So that's the punchline.

Dr. Poholek: That's the key. So tell us a little bit about that, where you started, and your career progress, and where you are now, and what your new goals are.

Dr. Carcillo: Sure, well, at that time, although antibiotics were given immediately, which stops the infection from spreading in your body because the way to understand it is these types of infections double every 30 minutes in your body. So if you let them keep doubling, you don't do so well. But at that time, it wasn't clearly understood that we could actually have an impact beyond that 98%. And when I came to start doing research on this in 1978, the mortality was 65%.

So the first thing that we looked at when I was a fellow was when these children come into the emergency room, is there something we could do to help them? And our first set of studies were showing these children actually were very low on fluid. So they had been sick for a while, not drinking. They might have had vomiting, they might have had diarrhea. And a large part of why they were dying rapidly for us was that they needed what we call fluid resuscitation. You can think of it like a car putting gasoline in the car. You need fluid to fill up the tank, essentially. So that was the first set of work we did. And that was the most dramatic, 'cause that dropped mortality from 65% to 10%.

Dr. Poholek: Wow.

Dr. Carcillo: And all the other improvements we've had since then is starting to understand other mechanisms. So we started with thinking about nature. And if you think about the horseshoe crab, which is the most prehistoric creature we have, they only have one cell circulating. And that one cell has to do all the things that all of our cells do. So it carries oxygen, it fights infection, and it causes clotting whenever you need it. And the interesting thing is that when the horseshoe crab, which if you go down to the beach, particularly New Jersey beaches, the Maryland beaches, you can see them all over the beach. Their blood is actually taken for something called a limulus lysate assay, which is used to test the purity of every product that you eat or use to make sure it's not contaminated with bacteria. And the way it works is it coagulates. So if there's endotoxin or part of a bacteria, it will come together and you'll see like a clump.

So as we thought about that, we said, okay, maybe what's happening is our body is clumping itself. Maybe when you get an infection, you're trying to send your cells there to stop the infections from spreading. And if it takes too long, then maybe you stop it from spreading, but you also stop the blood from getting to your body. So that's how we thought the first way that the fluids might be helping. You're kind of flushing that out, and it worked dramatically. But then the next thing we noticed was that patients were still losing their limbs, especially if it had been a prolonged period of time. And then we did the studies showing that they were clotting off their body.

So having seen that, we did work on plasma exchange. So if you are in that condition, you can take your child's plasma out of their body and put it in. Again, using the car analogy, it would be sort of like changing the oil. And when you did that, the clotting got better and they stopped losing their limbs. The next thing we thought about though was we saw that patients were now surviving, but then there were a group of patients who would die later of infection, which is what our study is about.

Dr. Poholek: Ah.

Dr. Srinath: Which brings into my first general question then, getting into your study that's upcoming is, can you tell us what precision medicine is?

Dr. Carcillo: Yeah, precision medicine is, when you see a patient who's sick, should you treat everyone the same way? Or should you look at the patient and see how they're different than other patients, and even how they're different from in the ICU from minute-to-minute, in the office from week-to-week. And if you think that all patients with an illness are the same, then you don't use precision medicine. You give them all the same thing.

But if, instead, you think that the illness that the patient has changes over time and is related to them as an individual, as a lot of what we're talking about now with dying of infection is related to an individual's response to the infection, then you need to use precision medicine to give the right medicine precisely to what that patient's problem is.

So you may be dying of infection, but why? Are you clotting? Do you have a low blood volume? Is your heart not pumping well? Are your blood vessels not doing well? Is your immune system not functioning? And then according to that, we treat you precisely.

Dr. Srinath: And how did the concept of precision medicine come up for septic shock management? And what I'm getting at is, is what do we understand about certain phenotypes of how patients respond?

Dr. Carcillo: Yes, exactly. So what we know is that we each are made of information, and that information in our body is called DNA, and that DNA sends the information out, and then we make proteins and we make fats, but we all do it just a little bit differently. And none of us is perfect, even though we may think we are, none of us is. And each of us has about 40, what we call variants, which are not perfect at all, that actually, you may not be sick now, but if you're exposed to something like an overwhelming infection, you'll manifest those variants. They are related to immunity, the ability to fight an infection. They're related to inflammation, your ability to turn off your inflammation. They're related to thrombosis, your ability to clot, but also to unclot. They're related to your ability to handle stress, your adrenal glands, as an example.

And all of these together work together to either help you, or if you have one of these pathogenic variants or defects, or to tell you the truth, many times our major problem right now are the medicines that we give, because many of the medicines we give, you know this well, and many of the procedures we do will prevent you from fighting infection or make you clot more, or make you over inflame, or make your stress system, your adrenal glands not work.

So the precision came from careful observation of, once we were resuscitating children, why were children acting differently? What's different about this child who dies from clotting? What's different about this child who dies from infection? We didn't know that until we understood the importance of early treatment. And once we treated everybody early, and a paper came out at this Center just last month, where the mortality rate was dropped from 2.4% to 1.7% in the Emergency Department by rapidly identifying the children, giving them fluid and antibiotics, supporting their heart and their blood pressure. So what is that other 1.7%? Why? Because now you're into the realm of genetic tendencies or environmental exposures interfering with those processes.

Dr. Poholek: So you have a new NIH-funded, multicenter precision medicine trial. Tell us what that trial is aiming to do.

Dr. Carcillo: Yes, it is called the Precise Trial. So we already talked about fluid resuscitation, supporting the cardiovascular system. And we already talked about taking care of the coagulation system, but then there's only two other systems left. One is the system that fights infection. And the other system is this system that turns off inflammation once you've killed your infection.

Now, that means, if you give a medicine that turns off inflammation but prevents you from killing infection to all the children, then half will benefit, half will be harmed. If you give a medicine to improve the ability to kill the infection, then half will be helped, the other half will be harmed if that medicine increases inflammation. So now, in the precise trial, we are doing laboratory tests which were developed here at Children's Hospital of Pittsburgh, and now have been brought by Dr. Mark Hall, who trained with us back in the early 2000s, which will tell you is your immune system not working well, and you can't fight infection, or are you over-inflamed?

Dr. Poholek: Can you tell us a little more about those tests, and precisely how you're able to distinguish those two things?

Dr. Carcillo: Sure. So if you take your blood out of your body, just a very, very little bit, like 1/10 of a teaspoon and you put it into a little test tube with some culture media so your cells can live in it, and you expose it to the same endotoxin that causes the horseshoe crab blood to clot, our blood won't clot, but it makes things called cytokines, and it'll make something called TNF. And what we've done with multiple studies is shown, if the level of TNF you make is less than 200, you cannot fight infection. It means that you're immune depressed.

Now, we've done studies showing that you can use a medicine that we use all the time in the hospital called granulocyte-macrophage colony-stimulating factor. They use it for children who have cancer when they get their chemotherapy. Their immune cells are depressed, and they use it to grow them back again. Well, we can use this at a very low dose, half the dose, over seven days, and we can restore your immune system and prevent you from not being able to fight infection or restore your ability to kill the infection.

And we did this single center trial here, which was published in 2011, showing that when we take those children looking at that test and we give them granulocyte-macrophage colony-stimulating factor, GMCSF, we not only restore their blood's ability to make TNF, but we actually decrease their whole body making inflammation.

So you remember, before I said, you need to use a medicine that helps you fight infection, but doesn't increase inflammation. So in this group of patients, you don't increase inflammation and you kill infection. And what we found was not only did you kill infection, but you prevented getting secondary infections, you prevented organ failure, and you reduced mortality.

Dr. Poholek: Hmm, that's really fascinating.

Dr. Carcillo: Now, on the other hand, in a second trial that we published five years ago now, there's a medicine called anakinra or Kineret, but it's interleukin one receptor antagonist protein. And this protein we make, again, in our own body, just like we do in GMCSF, but it reduces inflammation.

So there was an adult trial done in the 1990s, seeing if this medicine would be effective in people with sepsis, and it had no effect, but knowing what we know in 2020, or 2015 when we published the paper, we said, well, wait a second, maybe it's because of that phenomenon we said. They weren't using it precisely. They were using it on everybody. What if we identified patients who were over-inflamed and only looked at them in that study and go back and see.

And what we found was that if you had a ferritin level over 2,000 or organ failure of the liver and something called disseminated intravascular coagulation, but clotting problem and a metabolism problem, and you received anakinra, which is interleukin-1 receptor antagonist protein, your mortality was reduced to the same point as people who did not have the high ferritin and that organ failure pattern, which we call macrophage activation syndrome. It represents, in adults, about 6% of sepsis patients, and in children, 10% of sepsis patients, but the mortality rate's 10 times higher than any of the other patients. So in this small group of patients, you could have a very large impact.

So what we do in this trial is we identify children who are infected to the point that their organs are failing. And then we do the blood test. We take 50 microliters of blood and expose it to endotoxin to see if their TNF response is above or less than 200. At the same time, we look at the ferritin level to see if it's above 2,000 or below 2,000. If the child has a TNF response less than 200 and a ferritin less than 2,000, they are randomized into what is called the Grace Trial, where you get a placebo of salt water or saline versus GMCSF. Now, if your ferritin level is over 2,000, then you're randomized to placebo or the Anakinra or interleukin-1 receptor antagonist protein. And the outcome that we'll look at is resolution of organ failure.

Dr. Srinath: So this brings up, I'm just fascinated on how these medicines came about to lead you to think about precision medicine based on response rates. And I think the granulocyte-macrophage colony-stimulating factor story is quite fascinating. Could you detail how that medicine came about to even think about for its use, as just an example of your arms?

Dr. Carcillo: Yeah, well, the wonderful story is, they call it luck, is that at the time that I became interested was also the beginning of the molecular biology revolution. So all that money that you've been paying on your taxes to pay for research, the scientists, and some of those scientists were physicians, most not, figured out, if we go back to that DNA to the information that's in our body, can we maybe make proteins that we make in our body?

Remember, up until that point in time, the only way you could get a protein out of your body would be to take a lot of blood from you as a human, or from a horse or something like that, and fractionate out a protein. Well, that's both very expensive and very hard to accomplish, but in the molecular biology revolution, what happened was that a scientist was sitting next to hot springs. And he noticed that there was a bacteria in these hot springs. And he asked the question, how could this bacteria live in this hot spring? How could they make DNA? Because for us, for us to make DNA, our body temperature has to be our body temperature. But imagine if you were living all the time in this extreme heat.

And this scientist looked for the enzyme, which you use to make your DNA, your information, and asked the question, well, if this enzyme is working at this very high temperature, maybe if I get that enzyme and I put it at a high temperature, if I drop the temperature, it'll stop making DNA. And then if I raise it, it'll go up. And it's called DNA polymerase. And in fact, that's the test that people have been doing to test for COVID. So they take the RNA from COVID. They reverse transcribe it to DNA, and then they use this Taq polymerase test to make the protein.

Well, the next step was we could take the DNA from humans or animals and we could see all the genes that make all the proteins in our body. And so, at the time that I just became interested in this topic, over 30 years ago, was when they first walked the human genome. And that's how they discovered granulocyte-macrophage colony-stimulating factor. And that's how they discovered interleukin-1 receptor antagonist protein.

So they were discovered. And then the nice thing about the molecular revolution is you could also make them, so that was the next step, where you could actually make the DNA and bioengineer. So now, bacteria make the DNA, or yeast make the DNA. So that's how. So none of this would've been possible when I started. It wasn't even known.

Dr. Poholek: Yeah.

Dr. Srinath: That's fascinating.

Dr. Poholek: So in the last few minutes that we have, I just wanna come back to the precision medicine trial.

Dr. Carcillo: Yes.

Dr. Poholek: So roughly how many patients do you think you'll need to enroll? And I recognize it's multicenter. And about how long do you expect the trial to take before you have results that can distinguish between these two treatments, based on the patient populations and whether they have low TNF and need GMCSF, or whether they have high ferritin and need anakinra?

Dr. Carcillo: Great question. So it's a 1,000-patient study.

Dr. Poholek: Okay.

Dr. Carcillo: It's 24 centers throughout the US.

Dr. Poholek: Wow.

Dr. Carcillo: It's supposed to be a five-year study, but it's taken us a year to get it started. So we're gonna make it a four-year study. That comes out, if every center contributes equally, that would be one patient per month from every center that was involved. Now, it's possible that we'll need less than 1,000 patients. So maybe less. We expect to see 600 patients enrolled with the GMCSF trial, and 400 with the anakinra trial.

Dr. Poholek: Got it, got it. Well, thank you so much.

Dr. Carcillo: Great, thank you.

Dr. Poholek: For your time today.

Dr. Carcillo: Thank you so much.

Dr. Poholek: And for sharing this information with us. It's amazing to hear someone with this level of research experience, come and share with us where they started and where they are now. And of course, we're excited to have you back once you get some of those preliminary data from the trial.

Dr. Carcillo: Thank you so much. And it's a great pleasure, 'cause really, all this work was started and done and is still being done at Children's Hospital of Pittsburgh.

Dr. Poholek: Fantastic.

Dr. Carcillo: Should be very proud, and I love your work as well.

Dr. Poholek: Oh, thank you so much. Fantastic, thank you so much, Dr. Carcillo.

Dr. Carcillo: You're welcome.

Dr. Srinath: Thank you, Dr. Carcillo.

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