Invasive NTM Infections and Heater-Cooler Units Webinar

By: Centers for Disease Control and Prevention (CDC)

[ Intro Music ] Good afternoon and welcome to today's webinar, Invasive Nontuberculous Mycobacterium Infections Associated with Exposure to Heater-Cooler Units during Cardiac Surgery. My name is Abbigail Tumpey. I'm Associate Director for Communications Science for the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention. This webinar is a part of a series of infection control related webinars that CDC will be hosting with a variety of external partners and experts. Today's webinar features an expert panel, including Dr.

Joe Perz, Team Leader of Quality Standards and Safety, in the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention. Dr. Perz will address the risk of invasive NTM infection from exposure to heater-cooler units. Also joining us is Dr. Charles Daley. Chief of the Division of Mycobacterial and Respiratory Infection at National Jewish Health. Dr.

Daley will discuss clinical manifestations of invasive NTM infections and diagnostic and treatment strategies. Also joining us is Dr. Daniel Diekema, Director of the Division of Infectious Diseases at the University of Iowa Carver College of Medicine. Dr. Diekema will speak on identifying patients who may be at risk of NTM infection and mitigating risks to these patients. Also joining us to provide commentary is Dr. Keith Allen, Director of Research and Clinical Associate Professor of Surgery in the Mid America Heart and Lung Surgeons.

Dr. Allen will offer a perspective from a surgeon and a member of the FDA Circulatory System Devices Panel. Before we get started, I would like to cover a few housekeeping items. We welcome your questions. Please submit any questions or comments you have via our chat window located at the lower left-hand side of the webinar screen. You may submit these questions anytime during the presentation. All questions will be addressed after the presentation, as time allows. To ask for help, please press the raise hand button located at the top left-hand side of the screen, if you need to chat with a member of the meeting chairperson to assist with technical difficulties, or any concerns you have during this webinar.

Invasive NTM Infections and Heater-Cooler Units Webinar

And as a reminder, the audio for today's conference should be coming through your computer speakers. Please ensure that your speakers have the volume turned up. Now it's my pleasure to introduce Dr.

Michael Bell, Deputy Director of CDC's Division of Healthcare Quality Promotion. Dr. Bell. Thanks, Abbigail. Hi everybody, this is Mike Bell.

Thank you for joining us today. Today we're going to be hearing about a very specific issue related to medical devices and specific pathogens. But I wanted to start with sharing a perspective on device-associated infections in healthcare, and some of that bigger picture of what we're experiencing. I often say that the work that we do here is the science of unintended consequences. We all have the best intentions. I think that it's fair to say that across the spectrum of healthcare delivery, everyone who's involved in patient care wants patients to do well and have the best outcome possible. And many times we see innovations in healthcare that are intended to improve efficiencies, that are intended to have better convenience for patients and healthcare personnel, reduce invasiveness, and ultimately save lives. Unfortunately, in many instances, we find that there are unintended consequences of these innovations.

These can be broken down into several categories. And the few that I'll share with you today are these. One is the issue of misuse. Something that's designed for one thing but used inappropriately. Another is a challenge with maintenance and reuse of a device. And then finally there is the issue of a blind spot when it comes to infection risks. The first category, just as a quick review, can be beautifully illustrated with the insulin pen. An incredibly helpful device for patient to use at home.

But when it's accidently misused as a multi-patient device, by changing needles but using the same vial, that mistake leads to cross-transmission with hepatitis C virus and is a problem that we've seen again and again in this country. The second example can be captured with the issue of the reprocessing of duodenoscopes, a lifesaving device, something that reduces invasive care in inpatients. And yet what we're seeing is that the design makes it inherently challenging to clean and reprocess. Those failures have been demonstrated to result in transmission of pathogens from person to person. This is something that is built into the device in the sense that the engineers solved the problem, the problem of being able to look at a 90 degree angle inside someone's duodenum. And they did a very good job of that. But they weren't asked to solve the problem of reprocessing and ensuring that cleaning and disinfection occurs successfully every time. I won't spend more time looking at this example, but it goes directly to the current topic, which is heater-cooler units, a very important device that allows lifesaving surgeries to be performed.

And yet when you look at the device clearly, the question that was posed to engineers was, can you create a machine that circulates hot or cold liquid in a consistent way. But never were they asked to ensure that that device didn't create an infection risk. And I think that's the reality that we're dealing with today.

I think that, you know, in terms of what we need going forward, broadly speaking is emphasis on correct use, education, onboarding training, refresher training, and so on. Designs that promote successful maintenance. This may sound a little icky, but I pose to you the question, why do you think endoscopes are black? It's so they don't show soil, right. And that's probably exactly the opposite of what we actually want, even though from a marketing perspective, it's a bit of a disaster. And then finally, specifications for engineers that include minimizing infection risks. I think today's talk will go a long way towards describing the importance of that last piece. And so with that introduction, I'm very happy to hand this over to Dr.

Joe Perz. All right, thank you, Mike. On this first slide, we're just going to review several of the key characteristics of nontuberculosis mycobacterium, or NTM, as I'll be referring to it. I think one of the key things to emphasize is the slow-growing nature of these bacteria. Even the so-called rapid growing NTM are slow to grow in the environment, in a patient, and in the laboratory.

And so that introduces various challenges, as you'll hear. These bacteria are ubiquitous in surface water, tap water, and soil. They are opportunistic as pathogens, and as such, transmission is also associated with healthcare, where we have populations of immuno-compromised patients. We perform procedures like surgeries, which, by their nature, result in breaches in normal host defenses. And these bacteria exploit novel exposure pathways, as you'll see, including many that involve direct or indirect exposures to water.

The first strong evidence linking NTM infections to heater-cooler units, and specifically M chimaera, was offered in this article by colleagues from Switzerland. They described a prolonged outbreak of NTM infections after open chest surgery. There were invasive infections in six patients. They'd all undergone open chest procedures, had implants. And the infections or the procedures dated back to 2008 to 2012. There were delayed presentations of those infections. Because NTM are often associated with water, there was a thorough investigation of all possible water sources and pathways.

But the evidence that emerged actually singled out the heater-cooler unit. Next slide. Here's a schematic on the left side and then a picture of the device on the right. In the schematic, the device appears as representative of the box on the lower left-hand side. And the point of this is to remind folks that these devices are used during cardiothoracic surgical procedures that require cardiopulmonary bypass. These units produce fluids, which are introduced into the machine sometimes during an operation to replenish through an opening at the top of the machine. There are internal pathways for that water to be heated and cooled and then circulated to connect with other devices, such as cardioplegia machines, or heating and cooling blankets, as represented in the diagram.

There are also in the case of this unit, two fans, including a large fan in the base of the machine. And you can see the large grill on front and grills on the side as well. So around the time that the Swiss researchers made their report, we also had a report or rather a recall by the manufacturer of the Sorin 3T.

And that recall was actually not of the devices itself but rather their instructions for use. So this was classified by the FDA as an error in labeling. And information from the manufacturer indicated that or reminded, that while water from the device itself is not intended to contact the patient directly, under certain circumstances, due to fluid leakage and/or aerosolization, there may be a pathway created by which NTM could reach a patient's surgical site. And it's also probably worth pausing for a moment to remind the audience that, as part of that investigation in Switzerland, there was testing of not just the machine and the patient samples, but also air. So they did detect NTM, M chimaera specifically, in samples derived from air from the heater-cooler device. In the US, at about that time, we had reported to the Pennsylvania Department of Health a cluster of NTM infections among cardiac surgery patients in the state of Pennsylvania. Because of the growing awareness of this possible association, the heater-cooler units were immediately removed and replaced, even before CDC came on site to assist with the investigation. What our investigation did reveal were eight cases of invasive NTM.

It was a combination of M chimaera and then also other patients that couldn't be diagnosed to that level of speciation but fell into that general category, known as MAC, or M. Avium complex. The epidemiologic and lab findings also as was found in Switzerland, pointed to the heater-cooler unit as the source. We were able to replicate the findings in terms of positive aerosol generation with the machine running, the aerosols containing M chimaera specifically, M chimaera was identified from patients and environmental isolates, including water obtained from the machine, and they all matched. The hospital subsequently notified approximately 1300 patients. And that action in October 2015 initiated in October 2015 did result in the identification of several additional patients.

At that time, the FDA issued a safety communication. And the scope included all heater-cooler devices, and reminded users to adhere to manufacturers' instructions, to use only sterile or filtered water, to direct the exhaust from the machine away from the sterile field, to remove units with signs of contamination, and very importantly, emphasized the need for reporting of either contaminated units or infected patients. And so those types of reports have continued to come in. CDC also issued interim practical guidance in October of 2015, with the aim of amplifying the FDA alert and it provided guidance less so on the use of the device, as was found in the FDA alert, but more about identifying patients, trying to raise awareness. And our target audiences included health departments, hospitals, providers, and also patients. Here's a study published earlier in 2016. And I'm including it to illustrate I think it offers an interesting sort of visual illustration of the -- this was a smoke test, so it's not an aerosol, per se.

But the heater-cooler device, which is outlined in the red circle on the left side, after it is turned on, rather quickly was able to generate airflow that reached the surgical field. And that was despite this OR being outfitted with an Ultraclean Laminar Air Flow System. In addition, bacterial culture plates were found to be positive up to five meters from the unit. One more recent publication. This one is significant because it included an analysis not just of specimens from patients and units obtained around Germany, but it also included specimens obtained in the manufacturer's facility, which is located in Germany. And while there are not complete details, there is an indication from the authors that they found M chimaera in samples from the factory environment, and that those also matched when they compared them to the patients.

In early June of 2016, FDA issued recommendations for healthcare facilities and staff, updating their previous information and offering information specific now to the Sorin 3T unit. Aware of the results that I just described in terms of the factory contamination being evident, they are this alert reminded end-users that if they purchased and used a Sorin 3T unit prior to September 2014, that they should be aware and informed, the facility should inform clinicians and others of this potential risk, and to pursue follow-up and surveillance for cases following guidance that CDC had, at that point, recently revised. This slide is just a screenshot of our updated guidance for identifying patients at risk.

I won't talk much about this because Dr. Diekema will cover this topic when he presents a little later. And finally, in June of 2016, the FDA deemed an advisory committee, its Circulatory System Devices Panel, to discuss the issues and challenges around the heater-cooler devices and how best to manage that risk. One of the key I think discussion points was that the realization that despite outreach efforts, which had been substantial to that point, that awareness of heater-cooler infection risks remained low. And that the recommendation was that there needed to be escalation of that awareness across the clinical community. Today's webinar is one attempt at raising that awareness. I would encourage our viewers today to review this FDA website for an executive summary and other materials from that meeting. And with that, I'd like to turn it over to Dr.

Daley. Thank you. Thank you, Joe. Let's transition now to the clinical presentation, diagnosis, and then treatment of disseminated chimaera. I'd like to begin with four disclosures. I have received either grants or contracts from organizations related to the diagnosis and treatment of NTM's, such as Insmed, COPD Foundation, Cystic Fibrosis Foundation, and more recently, the FDA. So I'm going to try to first begin with a discussion of what's in a name and talk a little bit about this organism chimaera. We'll then switch to the clinical presentation and when to think about disseminated disease, and finally look at the diagnosis and treatment.

So as you pointed out, this is a slow-growing nontuberculosis mycobacteria. And I think it's also important to recognize that now there are over 170 species or subspecies of NTM. These are ubiquitous, as you noted. And interestingly they have low virulence. We consider these opportunistic pathogens. Usually we see them as a cause of chronic lung infection, mostly among people who have underlying lung disease, such as bronchiectasis or COPD.

But we also see it in a disseminated form of disease, but usually in the setting of extreme immunocompromised, such as in advanced AIDS or post transplant patients. Now, MAC, mycobacterium avium complex, is not just MAI anymore. There are 10 to 11 species that sit within the MAC complex.

And chimaera at the top is just one of those species. So chimaera is MAC, but it's very important that we be very specific when we talk about which species is causing the infection. How often do we see chimaera as opposed to other species of MAC? Well, in the region in which these infections were first described in the heater-cooler units, it turns out it's quite common. Among 97 patients between 2002 and 2006, in Germany, they found 69 isolates by the National Reference Laboratory. There were 166 different strains of mycobacterium intracellulare, and that had been identified using a 16S RNA base method, which is frequently used in the US. But it turns out, using a more specific sequencing method, that 86% of those that had been labeled as intracellulare were, in fact, chimaera. So in this particular region, this is a very common species of MAC.

We've looked at this, and I thank Max Salfinger, director of our lab, for this information. But to look at what we're seeing at National Jewish, almost 9000 isolates, using rpoB gene sequencing, we were able to identify seven mycobacterial species, to account for 80% or so of the isolates. 42% of those were either avium, intracellulare, or chimaera. So you can see that what we're seeing is the chimaera is less frequent than that what was reported in Germany, with only about 6% overall, and the least common of the three other species that we consider MAC. Does it matter which species? Well, there are data now that are starting to accumulate that suggest that we should be precise in our naming a speciation. If you look at acquisition of infection, M avium and M chimaera appear to be found in water. But it's not clear where intracellulare is coming from, because most of the intracellulare isolates from water are being identified as chimaera.

In terms of pathogenicity, however, at least in terms of pulmonary disease, intracellulare appears to be the most pathogenic, with chimaera being the less pathogenic. There's been some descriptions of variation in clinical presentation with intracellulare tending to present with more advanced pulmonary disease such as cavitary disease. And one study looked at treatment outcomes, noting that chimaera and M avium had a higher rate of clinical recurrence in intracellulare, although intracellulare, as I noted, may be more pathogenic. So actually understanding which species is infecting our patient is very important, and particularly in an outbreak setting.

When we think about it from the clinical side of pulmonary infection, patients who have mycobacterium chimaera usually present like most MAC patients, with a chronic cough, fever, very few specific signs in the laboratory. It's usually just signs of chronic infection. It's also important to note though that once we see chimaera in the lung, it is extremely unusual to see it disseminate outside of someone who is immunocompromised. Now, if we look at the case presentation of or clinical presentation of those reported in this chimaera outbreak, it's different. The symptoms are that more of a constitutional illness with less respiratory symptoms, except shortness of breath in some of the patients.

They often have splenomegaly or chorioretinitis. And often profound anemia with lymphocytopenia, thrombocytopenia, an elevated CRP, transaminases. And in some cases, there's been renal insufficiency. Also, very important to note, if you look at the time to presentation, from the time of the surgery to the time the patient presented with these symptoms, it was quite long, with a median of 21 months.

But even up to almost five years after the surgery. Making this something very difficult for clinicians because few of us would suspect that a surgery years ago would be presenting now with a disseminated chimaera. When you look at the manifestations, most of these patients have either prosthetic valve endocarditis or vascular graft infection. And their manifestations of disseminated disease include emboli, bone marrow involvement, splenomegaly, nephritis, as I mentioned, myocarditis, and even osteomyelitis.

So there have been delays in diagnosis, as you might imagine. And one is this long period from the index surgery to the clinical presentation. The other is the various clinical manifestations. Patients have presented with a lot of different combinations. And it's not just one clinical presentation that we must be looking for. Now, in some cases there's been a lack of appropriate cultures at the presentation. Of course, people weren't sending mycobacterial cultures initially.

And as Joe mentioned earlier, this is a slow-growing organism and can take weeks to grow and sometimes longer to get final identification. Believe it or not, even when it's grown in the patient's blood, there have been providers who did not believe the result and did not embark on therapy at that time. So diagnosis, it's going to take a long time from the time you think about it to get the diagnosis, from collection of the appropriate specimen. In this case it could be blood cultures, it could be urine cultures, tissue cultures. And this is an eight-plus week process, all the way to the time of identification and eventually drug susceptibility testing. If the laboratory, however, is not doing appropriate speciation, you will not even know that this is mycobacterium chimaera. The only way you will know is if the laboratory is using sequencing methods that can distinguish chimaera from intracellulare. And unfortunately, in most laboratories in the US, they do not do that.

So you think your patient has intracellulare, when, in fact, sequencing would show that they have chimaera. So how do we treate it? Well, this is the treatment algorithm for MAC in the setting of pulmonary infection. The most important clinical or laboratory information that you can receive beyond precise speciation is, is this a macrolide susceptible organism? If it is, then in pulmonary disease, we look to see whether there's cavitary disease. If there's no cavitary disease, we use three times weekly three-drug regimen. If there is cavitary, we use a daily regimen. If this is not a macrolide susceptible regimen, then we go to daily therapy. In that setting, we would consider IV amikacin, and we would also consider that additional parenteral agent, if there was cavitation present. If in the setting of macrolide resistance, we're going to be faced with needing other drugs, and you can see a list of potential drugs that have been used in such patients.

The reason I'm bringing up the issue of macrolide susceptibility is because it is critical in terms of the outcome of the patient. In pulmonary disease, if you have a macrolide susceptible patient that has noncavitary disease, we expect culture conversion in 80% of the time, in more extensive disease with cavities, less than 50%. But in the setting of macrolide resistance, if you don't do surgery or give a prolonged course of IV aminoglycoside, the culture conversion is close to 5%. So this is a huge issue. I bring it up because some people who discuss, maybe we should be trying to prevent disease in these patients by giving them macrolide monotherapy. We don't know if that would work.

It probably would not. And if it does result in macrolide resistance, the patient is probably going to be incurable. So then in the disseminated model, we have the same question, is it macrolide susceptible or not? But we would never give intermittent therapy in this setting. And I would strongly encourage the use of IV amikacin. In some of these patients, they have received months of IV amikacin, and that would probably be necessary at least getting to the point that you could we hope convert them and consider surgery. Now, this is a busy slide, but I just want to point out the outcomes in these patients. So these are 10 patients that were reported by Kohler with chimaera infections related to heater-cooler units. And if you look at each of those 10 that has a red box in that second column, those are patients that died.

Many of these patients had to have repeat surgery, in some cases multiple surgeries. So the outcome, despite starting in some cases very aggressive therapy, has not been good, with a very high mortality. So then why is it so difficult to treat? Well, there first is this delay in diagnosis, and this results in more widespread disease. This is an endovascular infection involving foreign material, presumably covered in a biofilm.

These are largely bacteriostatic drugs that we're using to treat chimaera. And we know in other patients that we see low serum drug concentrations, and I think particularly so in very ill patients. And of course, some of these -- well, all of these have comorbidities in terms of some form of heart disease, and by the time they present, they may have liver disease as well as nephritis, as noted. So this is a very difficult patient population to treat. I hope that with increasing awareness of this, we will be able to make the diagnosis earlier and get people on appropriate therapy much sooner than we've been able to do so far. So I'll stop with that, and I'll hand it over to Dan, Dan Diekema.

All right, thank you very much, Chuck. My job over the next 10 minutes is to discuss how to find cases, how to communicate risk for this infection, and how to reduce risk for infection after exposure to heater-cooler devices. So a lot of what I'll be describing comes out of our experience at Iowa after we detected a case of invasive mycobacterium chimaera in a patient who had received surgery using cardiopulmonary bypass at our institution. Once we confirmed that this patient had no other risk factors for mycobacterium chimaera, we immediately convened our hospital emergency incident command, as we would in any significant outbreak or potential outbreak, in order to get the right people around the table to assist with case finding, to assist with a communication plan, and to assist with other aspects of the outbreak investigation, including reducing risks for any further exposure. Within the next two weeks, we completed a lab-based look-back, developed a process for evaluation of exposed patients, notified public health authorities, the Joint Commission, the device manufacturer. We coordinated patient, provider, and media notifications. We removed our heater-cooler units from service, sampled them, and postponed elective surgery until we found a way to operate the devices outside of the operating room.

So you could say it was a very busy couple of weeks. So this was back in January of this year, and at that time we were taking all of these steps as a result of having identified a case linked to our hospital. However, in June of this year, as you heard earlier from Dr. Perz, the FDA issued a safety communication recommending that some of these steps, including provider notification and case finding, be performed at all institutions who use the device that has been implicated in the invasive M chimaera outbreak, the Sorin LivaNova 3T model, or at least those centers who use units that were manufactured prior to September of 2014.

So let's begin by discussing case finding. The CDC has excellent interim guidance on identification of possible cases, and that guidance is published at the URL that's at the bottom of this slide. The guidance begins with a laboratory assessment, to find any patients that have positive cultures for nontuberculosis mycobacteria, specifically mycobacterium avium complex, within which we find chimaera, from invasive samples like blood, bone marrow, or tissue samples. With this list you can proceed to a clinical assessment. Do any of these patients have those clinical manifestations described by Dr. Daley? Prosthetic device infection, valve, or graft, sternotomy infection, mediastinitis, bloodstream infection, or a disseminated inflammatory process, specifically a disseminated granulomatous inflammatory process. Which many of these patients have.

Finally, when you have patients that are identified by this lab in clinical assessment, they should have an exposure assessment. Do they in fact have history of exposure to cardiopulmonary bypass? Now, there are some limitations to this case finding approach that should be noted. First, we really don't have enough information yet from the global outbreak to know how far back to go with the laboratory look-back. Everyone agrees that it should be at least four years, but clearly there have now been cases identified up to six years after heater-cooler unit exposure. So I would recommend going further back, potentially up to six years or more. Secondly, laboratory-based look-backs alone are relatively low yield for a couple of reasons.

As most of ID clinicians are aware, sterile site cultures for mycobacteria or AFB are usually only obtained when recognized risk factors are present, like AIDS with a low CD4 count, or other very severe immunocompromise. Prior exposure to cardiopulmonary bypass in an otherwise immunocompetent host was really only recently recognized to be such a risk factor based upon this outbreak. And that is still not widely understood by clinicians. So it's very important to understand that active case finding is also required. Now, the CDC guidance does address this by noting that AFB cultures or mycobacterial cultures should be obtained in patients who are exposed to heater-cooler devices, who meet the clinical criteria that were described earlier, prosthetic, graft infection, endocarditis, etcetera. But also who have some of the general symptoms listed here on this slide.

Persistent fever of unknown etiology, night sweats, joint or muscle pains, weight loss, and fatigue. The guidance also suggests sending any mycobacterium avium complex isolates that are detected to a reference laboratory for species level identification. As Dr.

Daley mentioned, most hospital laboratories, even those that do a lot of mycobacterial work, do not do the sequencing required to differentiate the different species within the mycobacterium avium complex. So a couple of practical approaches we've also taken here for case finding, recognize the fact that many of these patients have been misdiagnosed as having sarcoidosis due to the histopathology findings of noncaseating granulomas in various organs. So an existing diagnosis of sarcoid in a previously exposed patient is also an indication to consider AFB cultures, similarly for a diagnosis of culture negative prosthetic valve endocarditis. We've also developed a best practice alert, or BPA, for our electronic medical record. This BPA fires for any patient who has had cardiopulmonary bypass and also has a diagnosis code for a febrile illness or who has fevers without known cause.

The BPA includes in its instructions on how to order AFB blood cultures, and includes instructions on how to order an ID consult. Now, for our patient notification, we use billing codes and OR logs to develop a list of all those who are exposed to a heater-cooler device, although those at highest risk for disseminated disease clearly are those with prosthetic valves or grafts. We decided to notify all patients who are exposed, including some who had the device on standby during the procedure. Our perfusionist told us that sometimes those devices were running even though they didn't end up having to be used. We decided to require a patient response to ensure that all had received notification and used a toll-free line staffed by an RN with a script and an algorithm that we had developed.

We called those who didn't respond to the letter within a set period of time. If the exposed individual who called in or who we connected with had symptoms, they were given the option to be evaluated in an NTM clinic or mycobacterial clinic that we had set up for this purpose, or to take the information from the letter we had sent to their personal physician. This is just an excerpt from the patient letter.

These letters were reviewed quickly for plain language and also translated into the preferred language of the patient. We also had translators online available for the 24/7 call line. Importantly, we also sent letters to all of our referring providers, because many patients post cardiothoracic surgery will get their follow-up locally. It included a detailed question and answer about the issue. And I should really add, I should have added this earlier, our colleagues at WellSpan Healthcare System in York, Pennsylvania, other colleagues who had dealt with this, as well as our CDC colleagues, particularly Dr.

Perz and Dr. Crist, were very helpful during this time and as we developed these materials. So I want to thank them.

We put out a media release as soon as we were sure that most patients and providers had received the letters so that they didn't hear about this issue first from the evening news. We also, of course, designated a small handful of media contacts to do interviews and to field questions. You can visit the website, an image of which is here, that we launched at about the time we did the notifications. Which includes the information we wanted to share with patients, providers, and the public, as well as links to CDC and FDA materials. The clinic we set up for patient evaluation was staffed by a physician's assistant, with an ID physician on site as well for consultation. We developed a checklist to help determine when cultures should be obtained, updated our policy for AFB blood culture collection, and we had to order additional blood culture bottles specifically for the AFB blood cultures. Which brings up lab capacity, which I think is a very big issue for your hospital if you're dealing with this situation. Very few hospitals have full service mycobacteriology laboratories.

Even in labs like ours that do a fair bit of mycobacteriology, most still send isolates out for a complete species level identification and for susceptibility testing. So you need to involve your lab director very early to help with questions about your capacity, for doing additional cultures, the need for send-outs, what laboratory you will be using for your send-outs. In our case the initial evaluation, which included AFB blood cultures on close to 200 patients, exceeded the capacity of our instruments, so we did have to switch over to a manual method for AFB culturing, the so-called isolator method, for a time during the initial aftermath. So very important to get your laboratory director involved early. So as part of our initial investigation, we removed our heater-cooler devices from the OR, performed water cultures. We found mycobacterium chimaera in the heater-cooler water circuits. We sent those organisms to National Jewish along with patient isolates for genome sequencing, to confirm genetic relatedness between the isolates from the heater-cooler unit and the patient. We also reviewed, of course, our cleaning and disinfection protocols to ensure that we had been meeting or exceeding all of the current manufacturer's instructions for use.

And then we developed or had our engineering team develop these pass-throughs, which was basically drilling a hole in the operating room wall and putting these, what are illustrated here, spaces through which the tubing could pass, so that our heater-cooler devices could be operated outside of the operating room, with the OR maintaining positive pressure. Which we felt would eliminate the ongoing risks to patients. Now, additional engineering solutions obviously are needed to ensure separation of heater-cooler device exhausts from OR air since not all operating room suites are have a configuration that makes it simple to remove the heater-cooler devices from the OR. So in summary, this outbreak presents several important challenges for case finding, for communication, and for risk mitigation.

For case finding, as I've mentioned, many patients receive their follow-up care locally, not where their surgery was performed. Symptoms are often quite nonspecific. And mycobacterial cultures are not routinely performed. Thus, I think it's almost a certainty that many of these cases are currently going unrecognized. For communication, we are still fairly early on in this outbreak. So there a lot of unknowns, unknowns about the degree of risk after exposure, about variables that are associated with increased risk, how to manage the infections once they're diagnosed, and how to improve outcomes that to this point, as Dr. Daley alluded to, really unacceptably high crude mortality rates of 50% or greater currently.

Our risk mitigation is also complicated. Once colonized with nontuberculosis mycobacteria, heater-cooler devices are extremely difficult if not impossible to decolonize. I've yet to see a disinfection method that's been reliably proven to be effective. Water cultures are also of questionable value, as many labs don't do them well. There's only a small number of labs I think that are good at doing them. And we're using one of those labs. But even so, we find that cultures flip back and forth between positive and negative.

And as Chuck mentioned, they take eight weeks to come back, so they're not immediately actionable. Finally, it seems clear that we need to try to achieve this goal of separating heater-cooler unit exhausts from operating room air, but there aren't simple solutions available at this time to do so. While we were able to move our units outside of the OR, clearly from discussion with colleagues, this is not possible everywhere. At a minimum, the FDA, as Dr. Perz alluded to, recommends directing the exhaust away from the OR field, preferably towards the OR exhaust vent. But complete elimination of risk is going to require redesign devices that do not produce bioaerosols under any circumstances if they're going to be used in an OR environment. So with that, I will pass the baton to whoever's next.

So our next speaker is Dr. Keith Allen, although we're having technical difficulties, so I'm not sure if Dr. Allen is going to be able to speak. So let's give it a second and see if he's able to join us here. So this is Abbigail Tumpey from CDC. Thanks for your patience. Hopefully now we have Dr. Allen available on the line.

Dr. Allen, do you want to take it from here? Yes. Are you able to hear me now? Yes, we can. Go ahead. Great. My name is Keith Allen, and I'm a cardiothoracic surgeon in Kansas City, and was part of the FDA panel that met recently to explore how to not only disseminate this information, but what, from a practical standpoint, you know, surgeons can do.

I think you heard really some very nice concise talks about not only the complexity of the problem but the challenges that it faces for not only the treating community but for cardiac surgeons. Because from a practical standpoint, heater-cooler units are used every single day in multiple rooms in cardiothoracic surgery. And at times, are actually used in other operations, such as liver or even renal transplant procedures. Some of the novel ways to try to isolate these, such as we saw in Iowa, aren't going to be effective in most operating rooms simply because the structure isn't there to be able to do that. And ultimately, design features are going to need to be incorporated into the equipment so you prevent any biological aerosolization of any fluid anywhere. As an example, we're very concerned in our operating room, we're not able to move our machines out.

And we've actually done some unique things in conjunction with the manufacturer to try to isolate and cone down that exhaust fan out into a HEPA certified air vent. Even those things aren't terribly successful, and it's really going to take a design feature. I think from a cardiac surgeon standpoint, for me this was a very big eye-opener. I think if you quarried most heart surgeons around the country, they would, quite honestly, have an ignorance of this problem.

I think while this may have been pertinent and had risen to a nice level in ID and in some of the CDC and FDA levels, somehow this information just wasn't disseminated out to heart surgeons. We've been fortunate in that in working with the FDA in an effort to try to continue to get more people involved and have a better understanding of what this problem is. We've got a paper that we'll be presenting at the American Heart Association in November and another paper at the Society of Thoracic Surgeons meeting in Houston in January, that will at least help alert surgeons to be on the lookout for this problem. And not just surgeons, but cardiologists. Because oftentimes, the surgeon, after six weeks, might not see their patient again, whereas a cardiologist or a medical doctor may be following these patients for the rest of their life. Thank you, Dr. Allen. And I think our final summary will come from Dr.

Mike Bell. Dr. Bell? Well, thank you everybody. I think that was a wonderful array of expert comment and insight. I just want to summarize by recapping very quickly here. We are dealing with life-saving devices. We are not in a situation where we can stop using these devices.

And if you look at the incidence of these outcomes compared with the number of successful surgeries, these remain very helpful important devices. Nonetheless, there is a potentially very large number of individuals exposed. The presentation, as you all heard, is very non-specific and potentially slow-moving. The pathogens grow slowly and have very specific diagnostic requirements. And so tying this altogether, I think as you just heard Dr.

Allen say, not only surgeons but in particular those people who follow patients after an open procedure of this sort need to maintain a high index of suspicion. Anytime they're seeing a patient with a persistent infectious seeming non-obvious process, and include cultures for acid-fast bacteria. You heard Dr. Diekema say that, you know, for a systematic look-back, this also involves partnering with the laboratory director to make sure that the ability to do that kind of culturing exists. But in particular, not just for look-backs but specifically when you're looking at someone with symptoms, getting cultures for acid-fast bacteria is a very important step. Otherwise, the diagnosis will not be made.

Lastly, I think interim solutions for the location of the machine, as you just heard, are not a perfect solution. Some places have removed the machine to a space outside the operating theater. Other places have devised containment systems to contain the outflow of air from the machine and direct the outflow of air away from the operating area. Those are solutions that are okay, but I think they are temporary until the underlying design can be improved. I think with that, I can hand it back to Abbigail who will look at questions. Thank you, Dr.

Bell. We have about seven minutes for questions, and we have a ton of questions coming in. I think with regards to top questions we're getting, it actually is around the issue of cleanability. I'm wondering if maybe Dr.

Diekema and Dr. Daley want to start, and then we'll have some of our CDC folks jump in. So Dr. Diekema, you talked about what happened to some of the devices that were used on these patients.

But once a unit is contaminated with NTM, is the unit cleanable? Hi. So I think that's a really it's a good question and a difficult one. The literature that's currently out there is not, in the clinical experience that places have had, is not particularly reassuring. That certainly you may with sort of more aggressive cleaning disinfection approaches suppress the level below the level of detection or intermittently be unable to detect it. But many people have had the experience of almost no matter what they do with these units, they eventually will find the same the organism again. One thing that is clear because of the propensity of these organisms to form biofilm and their extreme resistance to disinfection once that's happened, any attempt to eradicate from a unit would require complete replacement of all the internal tubing.

So if other faculty know of anything more recent from FDA or the manufacturer, I welcome their input. This is Keith Allen, and I would echo those comments. That I think once you have the biofilm, that disinfecting that biofilm without a complete changeover of the internal parts is going to be impossible. But I do think everybody needs to be made aware that this problem arose several years ago and has been ongoing for a number of years. And quite honestly, most perfusionists at heart centers probably were not following appropriate IFU on how to take care and maintain these equipment.

So I do think now within the perfusion community there are some very specific recommendations from all heater-cooler manufacturers on how to appropriately care for their devices. And the goal would be to prevent biofilm by keeping these devices up to date from the get-go. Great, thank you. The next question is for Dr. Joe Perz. Dr. Perz, you mentioned a couple types of heater-cooler devices that CDC has looked at. But has CDC looked at any other heater-cooler devices made by other manufacturers? Okay, CDC, of course, has, you know, received reports of both contaminated units and potentially infected patients.

I can say that we have not received reports of M chimaera infections or unit contamination with other brands and models. Another follow-up question we're getting quite a bit is with regards to other types of infections. Are we seeing any other types of infections associated with these particular units? No, you know, and I don't know if there's perhaps some kind of a detection bias that could be in play. I think that in principle, you know, we would imagine that other species of NTM could be transmitted, you know, by the same devices, by the same route. But we've not had any convincing reports to indicate that that's happened.

So our next question is for either Dr. Daley or Dr. Diekema. Should healthcare providers be using some sort of air filtering system for the exhaust on these devices? Go ahead. Well, from the infection control, you can have it. I think when Dr. Allen was talking about design modifications and engineering solutions, certainly one that would seem obvious would be, could one filter the exhaust such that mycobacteria could not get through and you'd prevent this bioaerosol.

I think the problem is jury-rigged solutions that individual institutions take that have the potential to interfere with the operation of the heater-cooler device are potentially problematic. And some of these devices move so much air that I'm not sure whether or not it would be feasible to have the filter, the exhaust, without interfering with the operation of the unit. So I agree that that would be potentially a great solution. Maybe others know, you know, more about the feasibility. But I think at this point, I'm not aware of anyone that's successfully done that. I know as we just heard from Dr.

Bell, that some institutions have tried to sort of contain the device or make sure that the exhaust is somehow routed out of the OR without mixing with the OR air. But I'm not aware of anyone that's slapped a HEPA filter on the unit. This is Chuck Dailey.

Can I just, there was a piece of that that was about healthcare workers. So a healthcare worker -- and I was looking at some of the questions. So healthcare workers should not be at very much risk from chimaera. I mean, it's -- we don't know of any healthcare workers who have been affected by these organisms working in the ORs.

So remember it's a fairly low virulent bug that we drink and probably shower with and get exposed to not infrequently. So I don't think that is a major concern. I think obviously the main concern are the patients. One of the things, this is Keith Allen again, and one of the issues that with redirecting flow even outside the operating room, the reason that we see these infections particularly on prosthetic materials is probably because while the prosthetic material is sitting on the back table waiting to be implanted, you have this aerosolized bioproduct drifting down onto the backfield that then lands on the device, and then it's subsequently implanted. So redirecting it, while it may be an idea to get it out of the operating room, redirecting it to other areas of the hospital, particularly where surgical products or supplies are stored or other equipment is stored, you may be, you know, paying Peter to buy Paul. So you may not be solving your problem. So thanks.

We're coming up on time and I want to make sure we cover some of this continuing education issue. So lastly, to receive continuing education for this webinar, you must complete and pass the post-test activity at 80%. A pop-up window post-meeting survey will appear when you close out of your webinar. The link to the CE post-test and evaluation is included in this page. If you happen to miss the pop-up page, you can access this information from a link we will send you via an email following today's webinar.

With that, I'd like to thank our speakers today for a very lively discussion. And thank you for all that you are doing to protect patients. Thank you. Thanks. Thank you.

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