Activity Transcript

Alexander Sah, MD: Hello, I'm Dr. Alexander Sah. I'm an orthopedic surgeon at Sah Orthopedic Associates at the Institute for Joint Restoration in Menlo Park, California. And we welcome you to this Medscape program titled, Syndromic Testing for Joint Infections: What Is It and Why Should It Matter to You?

I'm very pleased and privileged to be joined by Dr. Jay Parvizi, who's the James Edward Professor of Orthopedic Surgery at the Sidney Kimmel School of Medicine. He is also an orthopedic surgeon at the Rothman Institute at Thomas Jefferson University in Philadelphia, Pennsylvania. Welcome, Jay.

Javed Parvizi, MD, FRCS: Thank you.

Dr Sah: Over the next 30 minutes, we're going to be discussing diagnostic testing for joint infections with a focus on syndromic testing. But first, let's start off with a little background on joint infections. First, we'll talk about the clinical burden of joint infections. When you look at its impaired quality of life, comparable even to oncology patients, we know how severely impacted these patients are, if they get a periprosthetic joint infection. Infections can lead to life changing complications. They can lead to loss of joint function, prolonged hospitalization, as we know, pain management, and psychologic impact of fear, depression, anxiety. And this can last long after the patient has their infection cleared. It is a devastating complication to our elective joint replacements.

Furthermore, periprosthetic joint infection is even associated with mortality. And when you adjust for confounding factors, PJI is associated with 5x increased odds of one year mortality compared with an aseptic revision. And if you look on the graph on the right, you can see where infection falls in terms of other very common cancers, prostate cancer, melanoma, breast cancer, colorectal, and even lung cancer. The 5-year survivorship, you can see that the infection is right about in the fourth section, in terms of survivorship. So, we cannot take this lightly. Periprosthetic joint infection not only affects our patients early, but it can affect them late, and have very real and very impactful effects long after surgery. And even one year mortality, as you see in this slide here.

So, Jay, obviously we are thrilled to have you here today. You are an expert in infection and management and total joint replacement. And again, we really are privileged to have you. We would love to hear you discuss some of the different types of joint infections, and what makes them so challenging to diagnose.

Dr Parvizi: Sure. Thank you, Alex, for a kind introduction. It's a pleasure to be on this webinar with you. As you said, orthopedic infections, overall surgical site infections are devastating complication, particularly when they are associated with implants. So different types of infections that we talk about, obviously implant-related infections, periprosthetic joint infection of the knee, the hip, the shoulder, ankle. And then more and more of these joints we do in artificial joints, that is increasing. Any artificial material going into the body can be infected.

And then there is the native infections that we know about, septic arthritis, whether it be in the child or in adults, when there is infiltration of the organisms into the synovial tissue. And obviously, it's associated with acute inflammation, PMNs, et cetera, migrating to the side of infection. And we know that obviously that happens in the younger adults, when the metaphyseal development is in process. And also, the older adults can get it as well. And it is sometimes associated with inflammatory arthropathy. And usually these presents at emergency because the joint is hot, swollen. And if you let the infection go on for long enough, patients can develop systemic infection as well, which obviously will manifest in sepsis.

Then there are other types of infection that we probably don't even know about, but they exist. And these are subclinical infections of a joint that's presented with pain. We have seen classical exams of patients who go to a dentist and two weeks later, they develop infection of a joint. Probably some of those are what we call, acute on chronic. These patients probably had a chronic infection that was going on, but the bioburden wasn't large enough to manifest in a clinical infection, but with a second hit that comes along and results in that type of a problem. So, anything and anywhere in orthopedics you look, unfortunately you can get joint or bone infection.

Dr Sah: Jay, thank you for that. That is an excellent representation of what we look at as orthopedists and particularly joint replacement surgeons, and is certainly such a challenge as clinicians, to face how we evaluate these patients who come in with a painful joint.

Really, we would love to know, what are the things that are first in your differential when someone comes about with a painful and warm joint? And then, what are some of the clinical questions we face in the acute versus chronic settings? Because that is so different for these joint infection patients.

Dr Parvizi: Yeah, great question, Alex. Obviously very, very important. So, as you know, American Academy of Orthopedic Surgeons and the International Consensus Meeting and other organizations have all declared that any prosthetic joint presenting with pain should be considered to be infected, unless proven otherwise. So, any infected joint should really be investigated for infection because unfortunately or fortunate, the infection does not usually present with rip roaring, open wound and puss pouring out, et cetera. They are usually just painful joints that they present to us.

Now, I'm not saying every painful joint is infected. But it's very important for us to keep infection as the differential diagnosis for any prosthetic joint presenting to us clinically. And in fact, as it happens, infection is the number one cause of failure of total knees and also total hips. In the old days it used to be instability, for example, for total hip. But now based on Australian Registry in American Academy, the AJRR, infection is the number one cause of failure of both hips and knees.

Now, there are other reasons for a painful joint, which we know about. Sometimes aseptic loosening of the components, instability of the joint, possibly crystalline arthropathies, local tissue reaction, or adverse local tissue reaction that we see with release of cobalt and chromium particles. Fortunately, we don't see these very often, but where in osteolysis can also be there.

Now on the aseptic loosening, Alex, I want to draw our audience's attention to the recent developments in this field. What we've come to realize is that a lot of these so called, aseptic loosening cases, are actually infections that either were not investigated preoperatively properly. Or the diagnostic tests that we have are so basic and perhaps primitive that the diagnose of infection was missed. Some of these, and some will argue most of these aseptic loosening cases are also infection. So, those are some of differential diagnosis.

Now, you talk about the timing. The timing is interesting. As we all know about, we obviously see chronic infections, patient who had an implant put in their joint or spine or other parts of their body, and they present with loosening of the implant many years later. And unfortunately, there are other parameters associated with infection, elevated sed rate, elevated CRP. And when the aspiration is done, there is elevated neutrophil count. Neutral differential white cell count is elevated. And then of course, there are some biomarkers, synovial C reactive protein and alpha defense and leukocyte esterases, etc. These are all elevated. So, that is the chronic infection.

And then we also see sometimes, acute infections where a patient underwent a surgical procedure a week, two, three weeks ago. And they suddenly develop rip roaring, red joint that is filled with puss. The metrics that sort of separate that acute from the chronic is, one, is the timing from the index arthroplasty. Second is the cell count and neutrophil differential and the synovial fluid in an acute setting is much, much higher -- 10,000, 85% neutral differential versus 3,000 and 70% neutral differential. And then there is also the presentation of acute infection is usually much more florid, both in the joint and systemically. Some of these patients present with systemic sepsis, fevers, and unwell, et cetera.

Now the reason we make a distinction between acute and chronic as you know, is because the surgical solution is a little different. With some of these acute infections, we are likely to get away with what we call, DAIR, which is debridement and irrigation of a joint with retention of the implant. Whereas with chronic, patient has to undergo resection arthroplasty with either 1-stage or 2-stage exchange arthroplasty.

So, to summarize, we have the acute and the chronic. On the acute we have the acute hematogenous and also we have the acute postoperative infection. And the diagnosis of both of these situations, whether it's acute or chronic, is the same. You start with ESR, CRP, maybe D-dimer level in the serum. We aspirate the joint, send it for neutrophil differential, leukocyte, and leukocyte count, and then maybe a molecular marker, and then culture.

The problem is obviously that in 30, 40% of these cases the culture is negative, and we know that the patient is infected. I know we'll be covering this culture negative subject a little later in the interview. But it is one of the major issues we face with currently, that we are unable to isolate the infective organism in these patients.

Dr Sah: Oh, that's incredible, Jay. Thank you for that explanation. And you and Craig Della Valle have done such great work helping guide us as surgeons in how to work up these patients with their appropriate markers. And some of the challenge I think is, as you described, we have so many tests to help us make the decision process, which in one way, is a good thing. But on the other hand, it is because there is clearly no one definitive test. We still have to put together the whole package of tests and the clinical evaluation. So unfortunately, we don't have that one test that will tell us, yes or no, but we have to put everything together.

But the other things I found very interesting and always great to hear is, how important it is to reiterate that we have to remember infection and to rule it out for anyone who has a painful joint. No surgeon likes to hear that. We are probably much better at diagnosing infection of someone else's total joint than our own total joint. But clearly, it is imperative that we don't overlook that, and we run the test. Because again, as you said, the treatment, it's so different if we can pick something up early, rather than letting it become a chronic infection.

Point number two for our audience as you mentioned, was that a lot of those aseptic loosenings probably did have some infectious component. So, we should not forget that. And it just highlights how important it is to be very thorough in our workups to make sure that we're doing the right thing for these patients, and not treating an infected joint as an aseptic joint. And I don't think we can reiterate that enough.

But again, some of the challenges are, there are so many tests for ruling out infection. And I think as surgeons, we have to make sure we don't believe what we want to believe. Because as you mentioned, if 30 or 40% of cultures are negative, even though they are infected, we can't fool ourselves and make someone not be infected. But that being said, we have serum biomarkers, ESR, CRP, D-dimer, as you already mentioned, fibrinogen, interleukin 6, procalcitonin, and all these things we have available to look in the blood to try to put together the picture of whether there's suspicion of infection. And joint aspiration is key with the white blood cell count, PMN percentages, leukocyte esterase, all the things you have already described. And the cutoffs, which would be the difference for acute infections versus chronic or people right after surgery, how those numbers would be different. Certainly, important for the audience to remember.

The more recent synovial tests like alpha defensin and synovial CRP certainly have gained a lot of popularity. But I think some have had challenges in either ordering or cost, or time to turn around in terms of results. So again, nothing is without some disadvantage, but the more information we can gather, it can maybe help us with some of those challenging cases that are on the fence, so to speak.

And then of course, we have the culture-based tests. We have synovial fluid cultures, which we know have inherent issues and challenges trying to grow something out of a synovial fluid culture alone. We have the intraoperative tissue cultures. And then sonification. Certainly, that's become more popular and maybe gives us some better results as well. But you can see just from this table, there are so many different things that go into determining what is infection or not. And it's really figuring out how to put all those pieces together.

Dr Parvizi: Yeah, I totally agree with you, Alex. I think the culture, there are some strategies to try to optimize the yield of culture. And I think you just already alluded to synovial fluid may not have as much of a yield as tissue culture. And if you are going to use synovial fluid to take as much of the synovial fluid, put it in the pediatric bottles, and then send them to the lab and ask the lab to process this quickly. And as you know, the duration of or incubation period of cultural, so it determines our ability to isolate. So, the longer you keep them, the better it is. Sometimes the culture medium may have to be enriched in the lab to try to isolate some of these uncommon pathogens. Some pathogens like mycobacterium takes maybe up to three weeks to isolate fungus the same. C acne we know it is a slow growing organism that we don't see as often.

Your point about where to take the tissue samples is a very, very important one. I think we want to take representative samples. You are aware of studies that shows doing a swab of a draining wound is not a good practice. I hope people have abandoned doing that. So, you really need to open the joint, go deeper into the tissue, and take implant surfaces. Tissues in the vicinity of the implant and perhaps even do some of the swabbing, special swabbing of the implant itself and send it for analyses.

Sonication as you said, it has become popular mostly in Europe. We have in the U.S., institutions, and I am not sure if you have it available at yours or not, but we have struggled to make sonication work. Logistically, it's hard to sort of set it up. It has to go to the lab. We are worried about the contamination. The 50 CFU, that's been the threshold that the Europeans have determined, has sort not born out in some of the studies that have been done in the U.S. So, we don't sonicate. We obviously do synovial fluid plus the tissue culture.

But in recent years, and I know we will come to this in a second, but in recent years as you know, the entry of molecular markers, syndromic testing into this field has become incredible. I think has changed the game, at least for the culture negative cases, if not more. And that has really taken us to a different level, which I think is very, very encouraging.

Dr Sah: No, that is definitely exciting, and we look forward to learning more about that from you very shortly. And it's interesting, when we are taking all these tests and we're sending to our labs, you raise a great point that not every lab is the same. How your lab processes something might be very different than how I process it. How they handle it, putting synovial fluid in a little red top tube and giving it to someone to run it to the lab, you don't know if it's getting there in 30 minutes or three hours, and how they handle it afterwards.

So, the tip of putting in a pediatric tube, the tip of really talking to your lab, this may be your one sample that you can run. You have to make sure they don't lose it. You have to make sure that they run it appropriately. You have to make sure that they keep it on the plates long enough. All the things you mentioned are just great tips that as surgeons, we need to talk to our labs and make sure they are doing things the way we want to.

And now let's say we do diagnose the infection, Jay. I mean this might seem like an obvious question, but why is it important to identify the causative pathogen in these joint infections? And can you review what organisms we would typically see with our periprosthetic joint infections?

Dr Parvizi: Sure. Great question again. There are probably 4 main reasons why you would want to know the effective pathogen. Number 1, because the type of infected pathogen will influence the antimicrobial treatment that you will give to that patient, be it in the form of an antibiotic cement spacer or in resection or the extended intravenous or oral antibiotic that we will administer to the patient in the post-operative period. So, choosing the antimicrobial.

Number 2, it is very important for us in terms of antimicrobial stewardship to know the organism. Because in the absence of the organism we have to resort to a broad-spectrum antimicrobials, gram positive, gram-negative multiple antibiotics, and sometimes maybe in an antifungal agent. And this of course, all of these besides the cost, have the increased morbidity on the poor patients because it could result in liver renal and other toxicities. Not to mention the potential for use of broad-spectrum antimicrobials that could lead to emergence of antimicrobial resistance, or AMRs.

Number 3 reason is that studies show that when you isolate the organism and you target that organism, the results are better than if you are treating these patients blindly. And the number four is the psychological reason. You and I could put ourselves in the position of these patients who are coming to see the doctor, being told that they carry diagnosis of infection, which is similar to cancer, as you previously mentioned. And then you are telling the patient, "By the way, I don't know what you're infected with. If you don't know the organism, how are you going to decide which of these you're going to treat?" It's like telling a cancer patient, "I'm going to treat you, but I don't know what type of cancer you have."

So, those are the reasons we must strive towards isolating pathogen or pathogens that cause this dreaded complication in our patients. And we owe it to them to be able to isolate it prior to subjecting them to these drastic surgical and medical treatments.

Now, you asked also about the organism profile. Yeah, that's a great question. That has changed. We used to, I'm sure you remember the days where people would stand on the podium and say, "80% of infections are caused staph aureus." Well, it doesn't seem to be the case anymore because the more and more we look for organisms, some of these very, very unusual organisms we see. So, it's still Staph aureus is probably the most common.

And of course, the staph aureus comes under different banners. We have the coagulase negative staph, we have methicillin sensitive staph, we have methicillin resistant MRSA. Then gram positive organisms like streptococcus is not unusual. Staph epi is not unusual. We do see occasional Enterococcus. Then there are anaerobic organisms. The C acnes is a classical one that they see. And then of course, we see some polymicrobials. In fact, I believe majority of the infections are polymicrobial, and culture only isolates one organism.

We do see fungi, but there are rare organisms or some of these gram-negative organisms, such E coli, and Pseudomonas, et cetera. So just about any pathogen that causes infection in the human body can cause periprosthetic joint infection or orthopedic infection for that matter.

Dr Sah: And that's why it's so important to identify that organism. For all the points you raise, and you are absolutely right, we are seeing more infections with new bacteria we have not heard of before. And we may or may not have much experience in what antibiotics or how to treat it. And so, you are constantly learning as we are diagnosing more and more.

Now as surgeons, we always depend on culture. That is the gold standard. That is what everyone does. We have already talked about how there can be challenges to obtain the right culture, whether it's from fluid or tissue. But what are some of the other limitations of what cultures can do and cannot do in this regard?

Dr Parvizi: Yeah. I think part of the problem with culture is, number 1, only 2% to up to 10% of organisms known to mankind can actually be isolated by culture. So, 90% of the organisms that we know that exist cannot even be isolated by culture. Number 2, implant associated infections are difficult to culture because they usually exist in the form of biofilm, sessile, structure, very sophisticated. Organisms cover themselves under the umbrella of glycocalyx, difficult to penetrate, and difficult for antimicrobials to penetrate that barrier also. And because they are in a sessile form, they are not metabolically very active or they are not planktonic, at least we cannot isolate them.

And then Eddie Schwartz and others have shown that there is also a concept of internalization. When the organisms are hiding inside the osteoblasts, and we are unable to detect them. Or they are inside the canaliculi bone, hiding away and we are not able to pick them up. Culture picks up metabolically active, planktonic organism. All the stars have to line up for culture to work. So, it is not surprising that 40% of the cases, culture is negative.

Dr Sah: That is intimidating, Jay. It makes us seem like we are up against a losing battle. These organisms are outsmarting us and obviously the challenges upon us to try to figure out how to diagnose these slow and growing organisms, and these ones that want to hide, as you describe. That is certainly the challenge. And I think as you've done to explain the limitations of culture, what we all believe as the gold standard, it is certainly wonderful that this evening we can talk about some of the molecular tests, which you've alluded to before, to diagnose these periprosthetic joint infections.

And so, some of the things we're going to talk about will be targeted NGS, so figuring out how to amplify the DNA. You have to have a specific platform of analysis, so it compares against a curated database. But with these ways of sequence whole genomes and a way to apply them to mix microbial genomes where we have the ability to now compare again sequence databases, so much more information in a faster period of time.

Dr Parvizi: Yeah. So, Alex, that is exactly right. This recent study that came out, one of my previous research fellows, this was a study that spanned over 5 years with numerous, numerous high caliber academic institutions contributed cases into this. And the next generation sequencing at the time, was only for observational purposes because we were doing a study. But it has now become part of my practice. I think molecular mechanisms, molecular techniques will continue to evolve and provide better data for us.

But again, this highlights two things that we previously discussed together. One is that some or more of these infections are polymicrobial in nature. And because of culture being so primitive, we are unable to isolate more than one organism. And the second is the fact that culture negatives, you are able to see the signal of DNA. Because you are not relying on metabolic activity of these organisms but their DNA signature to be able to isolate them. So, administration of antibiotics, for example, that usually leads to a compromise in the outcome of culture, these molecular techniques are not a slave to that type of a situation. So very, very interesting study. Incredibly important. I think it is opening the door towards molecular techniques that will come our way.

And I think you already talked about, we talked about obviously the PCR, which is the 16S amplicon of the organisms, the shotgun metagenomics where you're doing a whole genome sequencing apply to the actual tissue sample that you receive. And recently, we all heard, and we have had the good news of knowing that syndromic multiplex PCR has been approved by the FDA, which has now become available. And as you know, that's multiple panel of organisms that you can pick from body fluids, such as joint fluid or tissue samples, hopefully. And I think it targets 39 pathogens and it does include Candida. And gram-negative organisms and gram-positive organisms, some of those common organisms that we know about. And that is really, really encouraging, in my opinion. And moving to the future, it will change the way we diagnose infection in the first place and the way we manage them as well.

Dr Sah: Yes, the technology is amazing, Jay, I must say. And it is giving us information that we previously could not have. There have been some comparisons of these joint infection panels with synovial fluid culture. Can you talk a little bit about the sensitivity and specificity of the two, and how that might benefit us as orthopedic surgeons ruling out infection?

Dr Parvizi: Yeah, absolutely. So, I think we are talking about the BioFire syndromic panel because that's the only one I'm aware of, the multiplex PCR that's actually been FDA approved and available for us to use. So, a couple of studies that I've seen in shape of posters, which I'm sure will culminate in a peer reviewed publication in the future, they actually compared the BioFire panel versus synovial fluid culture in 1,544 samples from adult and pediatric patient population. This included periprosthetic joint infection as well as the native septic arthritis ones.

And the sensitivity was over 90%. Specificity was nearly 100% for the BioFire panel. And then, there is also the ability to pick up the antimicrobial resistance genes compared to culture. And they were able to identify at least one organism in 15.7% of the synovial fluid specimens using the BioFire panel. And multiple types of organisms and a single specimen was also identified, included gram-negative, gram-positive in yeast. So, this study definitely showed a higher diagnostic yield for the syndromic panel than routine culture. And the success rate of 99.6% for obtaining valid results on initial specimen tests. So, this was very, very encouraging on a large sample size. And again, they compared the syndromic panel to routine culture, which I think is very, very important.

So, in this particular study that was presented at the IDWeek, they looked at 42 patients with acute joint infection. 26 were native joints and 16 were PJI. And they looked at the detection of the organisms. And interestingly, culture was positive in 88%. 39% of the time culture was negative. And the use of BioFire panel actually resulted in earlier initiation of targeted antimicrobial therapy. And transition to targeted therapy could start roughly 57 hours earlier per participant. So, I think that's a big deal, a very, very big deal.

Another 2020 publication, which was in Orthopedic Surgery was on Unyvero multiple multiplex PCR for diagnosis of PJI. This was a retrospective cohort of 57 patients who met the 2018 ICM criteria for periprosthetic joint infection and underwent the PCR testing with the Unyvero's i60 joint panel. Twenty-five samples were positive reducing the proportional culture negative PJI by 19%. So again, a whole spectrum of organism was isolated by this multiplex PCR showing the promise of the molecular techniques, as we move into the future.

Dr Sah: That's a great summary. Thank you so much, Jay, for that, on the recent literature. So, I cannot thank you enough for your time and participation this evening. We could talk all night learning from your expertise. This has been an incredible discussion. I know I have already learned a lot. But any final thoughts you had before we close this session?

Dr Parvizi: Well, thank you so much, Alex. First of all, thank you for your kind comments, and been giving me too much credit for this work. It has been a pleasure to converse with you.

But I think we both came to the same conclusion, and that is periprosthetic joint infection or orthopedic-related infections are difficult to diagnose. Look for them, otherwise you will not see them. And the diagnosis, expect to see culture negative cases. We need to be aware of the molecular techniques that are now available to help us isolate the organism. And we both felt that isolation of the organism is very important because of those reasons that we mentioned.

But the future is going to be very interesting and exciting. I think we are going to come to realize that majority of these infections are polymicrobial. And because of the primitive nature of culture, we were unable to really recognize that fact. So hopefully that will have an impact on the 20, 30% failure rates that we see after two stage exchange arthroplasties. So hopefully the future for our patients is brighter. And as we continue to explore science and bring these technologies into orthopedics, we will make a better decision for our patients and make their lives better.

Dr Sah: Jay, thank you so much for joining me today for this important discussion and enlighten us on what the future may hold and how to better treat our infection patients. And to the audience, thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.