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Pam Peeke, MD (Host):  Hello and welcome to the Society of Critical Care Medicine’s iCriticalCare Podcast. I’m your host, Dr. Pam Peeke. Today, we’re going to be talking about procalcitonin in COVID-19 and influenza related secondary bacterial infections. I’m really pleased to be joined by Dr. Michael Broyles who is a Doctor of Pharmacology, Director of Pharmacy and Laboratory Services at Five Rivers Medical Center in Pocahontas, Arkansas. And Dr. Eric Gluck, Director of Critical Care Services at Swedish Covenant Chicago in Chicago Illinois. Welcome Dr. Broyles and Dr. Gluck.

Dr. Gluck:  Great to be here.

Dr. Broyles:  Thank you, Dr. Peeke.

Host:  Wonderful and really thank you for being of service to all of your peers who are going to be listening in trying to understand this biomarker procalcitonin or PCT. You know it’s widely used to assess the risk of bacterial infection and the progression to severe bacterial sepsis and septic shock and this is done in conjunction with obviously other laboratory findings and clinical assessments. So, one of the things we look at is the change of PCT over time and whether or not this helps us determine our treatment modalities as well as mortality risk in patients with bacterial sepsis. So, I want to take a step back here for a moment, and really look at what is the pathophys and kinetics of procalcitonin. So, Cr. Broyles, you want to start?

Michael Broyles, PharmD (Guest):  Yeah, I’m going to let Dr. Gluck start on the pathophys part and I’ll kind of chime in on some of that and the kinetics if that’s okay.

Host:  Okay. Dr. Gluck, take it away.

Eric Gluck, MD (Guest):  Let’s forget about everything we learned about calcitonin, procalcitonin in medical school. And fast forward to some research that was done not that long ago which actually demonstrated that procalcitonin is a prohormone that is actually produced in larger quantities outside of the thyroid gland than inside the thyroid gland. And over a period of time, it was eventually discovered that this is a very unique biomarker which is released in response to bacteria interreacting with the toll receptors, toll-like receptors on the cell surface when bacteria are in the neighborhood. And so, this causes a internal cellular reaction with translocation of nuclear factor to the nucleus, unraveling of the DNA, production of messenger RNA and then the production of procalcitonin.

Now, in the normal cells, not the thyroid gland; there is no enzyme capable of breaking it down to calcitonin. So, it remains as procalcitonin and it is now widely believed that procalcitonin basically is a biomarker for bacterial sepsis, highly specific for bacteria, does not go up in viral infections, does not go up in protozoa infections or other infections. It is just a couple of fungal infections where there has some cross-reactivity. But it is a very sensitive and specific marker for bacterial infections when they’ve become a problem for your cellular reactions.

Host:  Excellent. Okay, that was fabulous. Now, Dr. Broyles take it away with the kinetics.

Dr. Broyles:  Yeah sure. So, the interesting thing is that for the procalcitonin to be made and released into the bloodstream, is what Dr. Gluck alluded to is that requirement for bacteria. Hence that is why we have such a high specificity for bacteria which is upwards of 94%. So, the beauty of this is procalcitonin is not stored in the cells. It has to be made as Dr. Gluck mentioned. That process takes generally three to six hours. Now most of the time, you will – if that bacterial infection is significant, you will get the release of procalcitonin into the bloodstream within three hours. But almost always within six hours. And so, there is lag time between when you see bacteria and you release procalcitonin. Now also unique to that is the fact that there’s not a mechanism that we know of that can block the production and release of procalcitonin which is very important.

And so, what’s also then important is that time to peak. In other words, once these cells see bacteria, how long does it take for them to peak out so to speak and that process or that timeframe is essentially 24 hours. They gave people dead gram negative bacteria endotoxin and saw how long did it take to make procalcitonin and it was 24 hours. So, we had rises in three to six, peaks in 24 and coincidentally, the half-life, the elimination half-life, the time for it to go down by half is also 24 hours. So, it’s very interesting to think about that. So, if I had a peak of 10 now, I had appropriate antibiotic therapy, then essentially, I would expect that value to be half tomorrow. So, that’s very important. So, literally with this kinetic property of procalcitonin, I can very quickly determine within two serial measurements the opportunity to stop antibiotics, to evaluate if my antibiotics are working or not working and then at some point in time, basically with an 80% reduction, actually an opportunity to stop antibiotics. So, it give us a lot of information based on that kinetics.

Host:  I love it. And I love how what both of you have said segues so beautifully into the next thing. And we’re really talking now about applications in practical medicine. So, when we’re talking about bacterial infections, let’s talk about secondary bacterial infections in terms of risk and mortality. So, we’re thinking about in the back of our minds, COVID, and when someone presents with COVID symptoms; how we’re looking at and trying to assess the presence of secondary bacterial infection upon admission. So, how do you proceed in terms of understanding the severity, the risk and mortality, in the back of your mind. Here comes the patient. They are being tested on admission. You do PCT testing on admission. It seems to be a valuable additional piece of information for early assessment to rule out a bacterial co-infection. How severe is this bacterial co-infection Dr. Gluck?

Dr. Gluck:  So, as it turns out, procalcitonin seems to be a direct response to the burden of bacteria in the body, in locations where they are not supposed to be or bacteria that are not supposed to be in the body. And so, there is almost a perfect dose response curve. The more bacteria you have, the higher the level of procalcitonin will be. And of course, the higher the bacterial burden; the more likely bad things will happen to your patients like septic shock. And so, this biomarker not only tells you that a bacterial infection is present; but it also tells you the bacterial burden to that individual patient. And that allows you to customize your therapy to a specific individual based on comorbidities, age, and other factors that might be going on.

Host:  Excellent. Can you talk about actual levels? Are there specific levels we’re looking for here for low risk of bacterial co-infection and adverse outcome versus high risk?

Dr. Gluck:  The normal level is less than 0.1 so the signal is very, very small to begin with. And a classical infection concern will be when the levels get typically outside of the intensive care unit above 0.25 but inside the intensive care unit; we usually use a cut off of 0.5. In massive infections with bacteremia, it is not impossible to see levels of anywhere between 100 and 500 with the highest recorded value that I’m aware of, of 10,000. So, this is a biomarker with a lot of breadth to it and so, you can see a very strong signal to noise ratio which makes it even more valuable.

Host:  All right. So, COVID is a virus. So, can PCT at all differentiate viral, atypical and typical bacteria in pneumonia?

Dr. Broyles:  There was a paper that was done by [00:09:29] and they looked at 1735 patients. And this was about three years ago. And what they were trying to do is actually in serial measurements, determining if these patients – basically if you could differentiate the type of infection. So, they had pure viral infection in these patients and of course with this number of patients, you only end up with an organism at 37, 38, 40% of the time. So, in this study, they had 409 patients in the viral group, PCT median value was 0.09. So, just as Dr. Gluck said, 0.1 or less. In the atypical bacteria group which they only had 67 patients. Their median PCT value was 0.2. Now that seems they are very close together.

I can tell you in our data, that we’ve looked at in over 5000 patients; our median PCT value in atypical bacteria infections such as mycoplasma, chlamydia and pneumonia is around 0.31. So, regardless, if you look at these numbers 0.09 and 0.2 while it seems small, that is actually statistically significant. Literally you can tell with an atypical organism which produces the least amount of procalcitonin of all the organisms, compared to a viral. Then if you look in typical organisms, which is what they did. They had 169 patients. Their median PCT value was 2.5. So, literally, they demonstrated that you can use PCT to differentiate is this infection viral versus atypical or typical bacteria which is very useful. And this is what we see over and over again. So, you’re actually using this to help you determine a viral versus a bacterial infection which is the whole key because if you look at the COVID data, in the COVID data thus far, 8% of the patients actually have a bacterial co-infection on admission. Now we’re talking on admission. But yet, somewhere in the neighborhood of 78 to 79% receive extended courses of antibiotic therapy. Obviously, there’s a mismatch and there’s that need that people are treating basically themselves versus the patient because there’s really not a need for it where we can use the tests to help us actually have better antimicrobial stewardship.

Host:  Wow. Okay Dr. Gluck, your thoughts.

Dr. Gluck:  I really would reiterate virtually everything that Mike has said. The beauty of this marker while you’re taking care of COVID patients, is that often when they don’t have a bacterial infection to begin with, they have non-remitting fevers and looking at the patient, examining the patient, looking at the x-rays, especially for pneumonias; it becomes a clinical nightmare trying to determine whether the fever that they are generating now is part of the original COVID infection or due to a superinfection. But if you do surveillance measurements of procalcitonin or even if you just do it when there is a clinical change, a significant increase of procalcitonin will tell you that you’re dealing with a bacterial infection. And then of course, once the levels are elevated, you can actually use those levels to demonstrate success in therapy. So, procalcitonin levels with a half life as Mike pointed out of about 24 hours when they go down to 80% of their peak level, you can actually stop antibiotics safely without fear of recurring infection. So you can actually limit antimicrobial exposure to all these patients. And on the outside chance that you pick the wrong antimicrobial, the procalcitonin levels will not go down and that will give you pause for concern, consider the possibility that you either need to change antibiotics or maybe, your bacteria are in a location that is protected from antimicrobial penetration like an abscess.

Host:  Excellent. Fantastic. Now what’s interesting here is that do you – in your experience, both of you, have you found PCT to be used widely to be able to be seen as an option that laboratories have to help clinicians manage patients with COVID-19? I’m just curious.

Dr. Gluck:  Well let me say that Mike and I are early adaptors of this, and we’ve been doing this probably both of us for more than ten years using procalcitonin. Initially, it was a difficult sell. People did not understand the pathophysiology of it. They were caught up in the procalcitonin calcitonin scenario. There was a lot of data but the data that was available was mainly European. I would say now though, over the last four to five years, the adaption of procalcitonin has really shown significant penetration in the hospitals in the United States to levels that are well over 60%, if I’m not mistaken. Mike could probably further comment on that.

Dr. Broyles:  Yeah, I would reiterate. I know before COVID, that the – it was around 60% and I think now that it’s somewhere close to 70, 70ish percent. But I would like to reiterate is that I think while it’s there, I think a lot of people have not had the appropriate education and they don’t use the test to its maximal potential or use it fully. The one thing that I would like to drive home over and over again is this whole concept of education. It’s not a pregnancy test, yes, no. It is a test that needs to be understood and if you understand why it does what it does, it’s incredibly useful. There’s a lot of information you can garner from it. But a protocol is also very important. Because if not clinicians, each clinician will say and I hear this over and over again, well my patient is sicker, or I just don’t feel comfortable or you have any number of reasons why you don’t want to follow this. But the end thing is that we have to be better stewards. I mean it’s suggested by the year 2050, if we continue to do what we do now; 10 million people will die from multi-resistant infections annually. That will be the leading cause of death in the world. That will exceed cancer deaths by 1.8 million. So, we need these tools such as procalcitonin that need to be understood and we need to integrate that in a practice. We’re not saying it’s the sole solution, but it’s a huge opportunity to look at this picture because we all know that all the other biomarkers are primarily inflammatory where we had this high specificity for procalcitonin which makes it so useful.

Host:  This is fabulous. Because you’ve hit upon both of you have hit upon really beautifully a number of major issues with regard to medical practice here. One is really reigning in the use of antibiotics when they are truly not needed. And I think that – I think maybe all of us could agree that when COVID really hit, there was so much panic and there was so much worry; that a lot of people were jumping the gun and were overutilizing antibiotics when people came in with strange fevers and they were coughing and they had significant shortness of breath and again, the strange x-rays that we now understand so much better. I think the use of PCT is going to end up being a very useful guide to the appropriate use of antibiotics, guiding you not just upon admission but all throughout the hospital stay. Because obviously, things are going to be changing dynamically.

Also, to let people know, let practitioners know that this is an option out there. I still think we’re talking about 60 and 70%, what about the others. Why aren’t they using PCT? Why aren’t they getting educated? And I think the word needs to get out and hopefully this podcast will help inform people about that. So, I think that what you’ve shared today is absolutely fabulous. I think you’ve really hit upon some high notes on the pathophysiology, the kinetics, differentiation between viral, atypical, and typical bacteria pneumonia, the incidence and the risk and mortality that’s associated with secondary bacterial infection and really the use of PCT is such a valuable tool across the board. And in this case, specifically with COVID-19. I’ like to now reach out to each one of you and as you’re talking to peers, how about a final note that you’d like to share that you thought maybe wasn’t covered or that you really want to reiterate as we’re informing our peers.

Dr. Gluck:  Well if I could just go first, I think when I’m working especially in the intensive care unit, one of the things I want to do is I want to get the right answer and I want to feel comfortable that I’ve gotten the right answer. For the longest time, in my career, I have to rely on white count and fevers and maybe bandemia to diagnose bacterial infections knowing full well from the SIRS data that these would need a sensitive nonspecific, but I was trying to accomplish. And finally, a new biomarker which actually tells us what the cells are thinking if I can anthropomorphize that, what the cells are thinking about what’s going on in their environment, a biomarker which is very sensitive and very specific to bacterial infections is now available. It doesn’t replace clinical judgement or some other lab tests, but it does add significantly to the confidence in making diagnosis and therefore reducing physician’s anxiety at the bedside.

Host:  And Dr. Broyles?

Dr. Broyles:  Sure, two points if I would. One is I would like to talk about the risk assessment with the secondary bacterial infection. So, there were a couple of papers that were published. The one that I’ll mention, there is one by Chan et al that was published in April and they looked at almost 1600 patients and they looked at basically they used a multivariant Cox regression analysis to determine what the risk factors were. And as you would expect age greater than 75 with a hazard ratio of 7.86. And you go down age 65 to 74, 3.4 and cardiovascular disease and diabetes and like. But what was most interesting, the greatest risk factor for severity of illness and for mortality was a procalcitonin greater than 0.5. That has a ratio with 8.72. And hence the need to know on admission, does this patient have a secondary bacterial infection and as that patient goes through their course of stay, if they progress through their stay, did they develop one during that stay. And so that’s why it’s so important to use a toll like this.

And then the second point I’d like to drive home is that this is a serial test. It’s not a one and done. We don’t do one troponin, we don’t want – we want to – we do more than one and it’s the same thing with procalcitonin. We are going to do more than one because it’s looking at that change in bacterial burden over time. Which provides us that better clinical picture.

Host:  Excellent. Fantastic. Everyone, I’ve been joined by Dr. Michael Broyles who is Director of Pharmacy and Laboratory Services at Five Rivers Medical Center in Pocahontas, Arkansas and Dr. Eric Gluck, Director of Critical Care Services at Swedish Covenant Chicago in Chicago, Illinois. Thank you so much Dr. Broyles and Dr. Gluck and this concludes another edition of the ICriticalCare Podcast. For the iCriticalCare Podcast, I’m Dr. Pam Peeke.