anemia drugs

[ intro music ] good afternoon and welcometo today's webinar, invasive nontuberculous mycobacteriuminfections associated with exposure to heater-cooler units during cardiac surgery. my name is abbigail tumpey. i'm associate director forcommunications science for the division of healthcare quality promotion at thecenters for disease control and prevention. this webinar is a part of a seriesof infection control related webinars that cdc will be hosting with a varietyof external partners and experts.

today's webinar features an expertpanel, including dr. joe perz, team leader of quality standards and safety,in the division of healthcare quality promotion at the centers for diseasecontrol and prevention. dr. perz will address the risk of invasive ntminfection from exposure to heater-cooler units. also joining us is dr. charles daley. chief of the division of mycobacterial andrespiratory infection at national jewish health. dr. daley will discuss clinicalmanifestations 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 iowacarver college of medicine. dr. diekema will speak on identifyingpatients who may be at risk of ntm infection and mitigating risks to these patients. also joining us to provide commentaryis dr. keith allen, director of research and clinical associate professor of surgeryin the mid america heart and lung surgeons. dr. allen will offer a perspectivefrom a surgeon and a member of the fda circulatory system devices panel. before we get started, i would liketo cover a few housekeeping items. we welcome your questions.

please submit any questions or commentsyou have via our chat window located at the lower left-hand sideof the webinar screen. you may submit these questionsanytime during the presentation. all questions will be addressed afterthe presentation, as time allows. to ask for help, please press the raise handbutton located at the top left-hand side of the screen, if you need to chat with amember of the meeting chairperson to assist with technical difficulties, or anyconcerns you have during this webinar. and as a reminder, the audio fortoday's conference should be coming through your computer speakers.

please ensure that your speakershave the volume turned up. now it's my pleasure to introducedr. michael bell, deputy director of cdc's divisionof 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 hearingabout a very specific issue related to medical devices and specific pathogens.

but i wanted to start with sharing a perspectiveon device-associated infections in healthcare, and some of that bigger pictureof what we're experiencing. i often say that the work that we do hereis the science of unintended consequences. we all have the best intentions. i think that it's fair to say that acrossthe spectrum of healthcare delivery, everyone who's involved in patientcare wants patients to do well and have the best outcome possible. and many times we see innovations in healthcarethat are intended to improve efficiencies, that are intended to have better conveniencefor patients and healthcare personnel,

reduce invasiveness, and ultimately save lives. unfortunately, in many instances, we find that there are unintendedconsequences of these innovations. these can be broken downinto several categories. and the few that i'll sharewith you today are these. one is the issue of misuse. something that's designed for onething but used inappropriately. another is a challenge withmaintenance and reuse of a device. and then finally there is the issue of ablind spot when it comes to infection risks.

the first category, just as a quick review, canbe beautifully illustrated with the insulin pen. an incredibly helpful devicefor patient to use at home. but when it's accidently misused as amulti-patient device, by changing needles but using the same vial, that mistake leadsto cross-transmission with hepatitis c virus and is a problem that we've seenagain and again in this country. the second example can be captured with theissue of the reprocessing of duodenoscopes, a lifesaving device, something thatreduces invasive care in inpatients. and yet what we're seeing is that thedesign makes it inherently challenging to clean and reprocess.

those failures have beendemonstrated to result in transmission of pathogens from person to person. this is something that is builtinto 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 problemof 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 surgeriesto 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 circulateshot or cold liquid in a consistent way. but never were they asked to ensure thatthat device didn't create an infection risk. and i think that's the realitythat we're dealing with today. i think that, you know, in terms of what weneed going forward, broadly speaking is emphasis on correct use, education, onboardingtraining, 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 theopposite of what we actually want, even though from a marketingperspective, it's a bit of a disaster. and then finally, specifications for engineersthat include minimizing infection risks. i think today's talk will go a long way towardsdescribing the importance of that last piece. and so with that introduction, i'm veryhappy to hand this over to dr. joe perz. all right, thank you, mike.

on this first slide, we're just going toreview 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 emphasizeis the slow-growing nature of these bacteria. even the so-called rapid growing ntmare slow to grow in the environment, in a patient, and in the laboratory. and so that introduces variouschallenges, as you'll hear. these bacteria are ubiquitous insurface water, tap water, and soil. they are opportunistic as pathogens, andas such, transmission is also associated with healthcare, where we havepopulations of immuno-compromised patients.

we perform procedures like surgeries, which, by their nature, result inbreaches in normal host defenses. and these bacteria exploit novelexposure pathways, as you'll see, including many that involve director indirect exposures to water. the first strong evidence linking ntminfections to heater-cooler units, and specifically m chimaera, was offered inthis article by colleagues from switzerland. they described a prolonged outbreak ofntm infections after open chest surgery. there were invasive infections in six patients. they'd all undergone openchest procedures, had implants.

and the infections or the proceduresdated back to 2008 to 2012. there were delayed presentationsof those infections. because ntm are often associated withwater, there was a thorough investigation of all possible water sources and pathways. but the evidence that emerged actuallysingled out the heater-cooler unit. next slide. here's a schematic on the left side andthen a picture of the device on the right. in the schematic, the deviceappears 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 duringcardiothoracic surgical procedures that require cardiopulmonary bypass. these units produce fluids, which are introducedinto the machine sometimes during an operation to replenish through an openingat the top of the machine. there are internal pathways for that water to beheated and cooled and then circulated to connect with other devices, such ascardioplegia machines, or heating and cooling blankets, asrepresented in the diagram. there are also in the caseof this unit, two fans,

including a large fan inthe base of the machine. and you can see the large grill onfront and grills on the side as well. so around the time that the swiss researchersmade their report, we also had a report or rather a recall by themanufacturer of the sorin 3t. and that recall was actually not of the devicesitself but rather their instructions for use. so this was classified by thefda as an error in labeling. and information from the manufacturerindicated that or reminded, that while water from the device itself isnot intended to contact the patient directly, under certain circumstances, due tofluid leakage and/or aerosolization,

there may be a pathway created by whichntm could reach a patient's surgical site. and it's also probably worth pausing fora 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 chimaeraspecifically, in samples derived from air from the heater-cooler device. in the us, at about that time, we hadreported to the pennsylvania department of health a cluster of ntm infectionsamong cardiac surgery patients in the state of pennsylvania.

because of the growing awarenessof this possible association, the heater-cooler units were immediately removedand replaced, even before cdc came on site to assist with the investigation. what our investigation did revealwere eight cases of invasive ntm. it was a combination of m chimaera and thenalso other patients that couldn't be diagnosed to that level of speciation butfell into that general category, known as mac, or m. avium complex. the epidemiologic and lab findingsalso as was found in switzerland, pointed to the heater-cooler unit as the source.

we were able to replicate the findingsin terms of positive aerosol generation with the machine running, the aerosolscontaining m chimaera specifically, m chimaera was identified from patients andenvironmental isolates, including water obtained from the machine, and they all matched. the hospital subsequently notifiedapproximately 1300 patients. and that action in october 2015initiated in october 2015 did result in the identification ofseveral additional patients. at that time, the fda issueda safety communication. and the scope included all heater-coolerdevices, and reminded users to adhere

to manufacturers' instructions, to use onlysterile 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, emphasizedthe need for reporting of either contaminated unitsor infected patients. and so those types of reportshave continued to come in. cdc also issued interim practicalguidance in october of 2015, with the aim of amplifying the fda alertand it provided guidance less so on the use of the device, as was found in the fda alert, but more about identifyingpatients, trying to raise awareness.

and our target audiencesincluded health departments, hospitals, providers, and also patients. here's a study published earlier in 2016. and i'm including it to illustrate ithink it offers an interesting sort of visual illustration of the -- this was asmoke test, so it's not an aerosol, per se. but the heater-cooler device, which isoutlined in the red circle on the left side, after it is turned on, rather quickly was able to generate airflow thatreached the surgical field. and that was despite this or being outfittedwith an ultraclean laminar air flow system.

in addition, bacterial culture plates were foundto be positive up to five meters from the unit. one more recent publication. this one is significant because it included ananalysis not just of specimens from patients and units obtained around germany, butit 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 thefactory environment, and that those also matched when they compared them to the patients. in early june of 2016, fda issuedrecommendations for healthcare facilities

and staff, updating their previous information and offering informationspecific now to the sorin 3t unit. aware of the results thati just described in terms of the factory contamination being evident,they are this alert reminded end-users that if they purchased and used asorin 3t unit prior to september 2014, that they should be aware and informed, thefacility should inform clinicians and others of this potential risk, and to pursue follow-upand surveillance for cases following guidance that cdc had, at that point, recently revised. this slide is just a screenshot of our updatedguidance for identifying patients at risk.

i won't talk much about this becausedr. diekema will cover this topic when he presents a little later. and finally, in june of 2016, thefda deemed an advisory committee, its circulatory system devices panel,to discuss the issues and challenges around the heater-cooler devicesand how best to manage that risk. one of the key i think discussionpoints was that the realization that despite outreach efforts, whichhad been substantial to that point, that awareness of heater-coolerinfection risks remained low. and that the recommendation wasthat there needed to be escalation

of that awareness across the clinical community. today's webinar is one attemptat raising that awareness. i would encourage our viewers today to reviewthis fda website for an executive summary and other materials from that meeting. and with that, i'd like toturn it over to dr. daley. thank you. thank you, joe. let's transition now to theclinical presentation, diagnosis, and then treatment of disseminated chimaera.

i'd like to begin with four disclosures. i have received either grants or contractsfrom organizations related to the diagnosis and treatment of ntm's, suchas insmed, copd foundation, cystic fibrosis foundation,and more recently, the fda. so i'm going to try to first beginwith a discussion of what's in a name and talk a little bit aboutthis organism chimaera. we'll then switch to the clinical presentationand when to think about disseminated disease, and finally look at the diagnosis and treatment. so as you pointed out, this is aslow-growing nontuberculosis mycobacteria.

and i think it's also importantto 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 chroniclung infection, mostly among people who have underlying lung disease,such as bronchiectasis or copd. but we also see it in a disseminated formof disease, but usually in the setting of extreme immunocompromised, such as inadvanced aids or post transplant patients.

now, mac, mycobacterium aviumcomplex, is not just mai anymore. there are 10 to 11 species thatsit within the mac complex. and chimaera at the top isjust one of those species. so chimaera is mac, but it's very importantthat we be very specific when we talk about which species is causing the infection. how often do we see chimaera asopposed to other species of mac? well, in the region in which theseinfections were first described in the heater-cooler units, itturns out it's quite common. among 97 patients between 2002 and2006, in germany, they found 69 isolates

by the national reference laboratory. there were 166 different strainsof mycobacterium intracellulare, and that had been identified using a 16s rnabase method, which is frequently used in the us. but it turns out, using a morespecific sequencing method, that 86% of those that had been labeledas intracellulare were, in fact, chimaera. so in this particular region, thisis 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 atnational jewish, almost 9000 isolates, using rpob gene sequencing, we were ableto 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 seeingis the chimaera is less frequent than that what was reported ingermany, with only about 6% overall, and the least common of the threeother species that we consider mac. does it matter which species? well, there are data now that arestarting to accumulate that suggest that we should be precisein our naming a speciation. if you look at acquisition of infection, m aviumand m chimaera appear to be found in water.

but it's not clear whereintracellulare is coming from, because most of the intracellulare isolatesfrom water are being identified as chimaera. in terms of pathogenicity, however, atleast in terms of pulmonary disease, intracellulare appears tobe the most pathogenic, with chimaera being the less pathogenic. there's been some descriptions ofvariation in clinical presentation with intracellulare tending to present with more advanced pulmonarydisease such as cavitary disease. and one study looked at treatmentoutcomes, noting that chimaera

and m avium had a higher rate ofclinical recurrence in intracellulare, although intracellulare, as inoted, may be more pathogenic. so actually understanding which species isinfecting our patient is very important, and particularly in an outbreak setting. when we think about it from theclinical side of pulmonary infection, patients who have mycobacterium chimaerausually present like most mac patients, with a chronic cough, fever, veryfew specific signs in the laboratory. it's usually just signs of chronic infection. it's also important to note thoughthat once we see chimaera in the lung,

it is extremely unusual to see it disseminateoutside of someone who is immunocompromised. now, if we look at the case presentation ofor clinical presentation of those reported in this chimaera outbreak, it's different. the symptoms are that more of a constitutionalillness with less respiratory symptoms, except shortness of breathin some of the patients. they often have splenomegaly or chorioretinitis. and often profound anemia with lymphocytopenia, thrombocytopenia, an elevatedcrp, transaminases. and in some cases, there'sbeen renal insufficiency.

also, very important to note, if youlook at the time to presentation, from the time of the surgery to the timethe patient presented with these symptoms, it was quite long, with a median of 21 months. but even up to almost fiveyears after the surgery. making this something very difficult forclinicians because few of us would suspect that a surgery years ago would bepresenting now with a disseminated chimaera. when you look at the manifestations, most of these patients have either prostheticvalve endocarditis or vascular graft infection. and their manifestations of disseminateddisease include emboli, bone marrow involvement,

splenomegaly, nephritis, as i mentioned,myocarditis, and even osteomyelitis. so there have been delays indiagnosis, as you might imagine. and one is this long period from the indexsurgery to the clinical presentation. the other is the variousclinical manifestations. patients have presented with alot of different combinations. and it's not just one clinicalpresentation that we must be looking for. now, in some cases there's been a lack ofappropriate cultures at the presentation. of course, people weren't sendingmycobacterial cultures initially. and as joe mentioned earlier, this is aslow-growing organism and can take weeks to grow

and sometimes longer to getfinal identification. believe it or not, even when it's grown inthe patient's blood, there have been providers who did not believe the result and didnot embark on therapy at that time. so diagnosis, it's going to take a longtime from the time you think about it to get the diagnosis, from collectionof the appropriate specimen. in this case it could be blood cultures, itcould 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 doingappropriate speciation, you will not even know

that this is mycobacterium chimaera. the only way you will know is if thelaboratory is using sequencing methods that can distinguish chimaerafrom intracellulare. and unfortunately, in most laboratoriesin the us, they do not do that. so you think your patient hasintracellulare, when, in fact, sequencing would show that they have chimaera. so how do we treate it? well, this is the treatment algorithm formac in the setting of pulmonary infection. the most important clinicalor laboratory information

that you can receive beyond precise speciationis, is this a macrolide susceptible organism? if it is, then in pulmonary disease, we lookto see whether there's cavitary disease. if there's no cavitary disease, we usethree times weekly three-drug regimen. if there is cavitary, we use a daily regimen. if this is not a macrolide susceptibleregimen, then we go to daily therapy. in that setting, we would consider ivamikacin, and we would also consider that additional parenteral agent,if there was cavitation present. if in the setting of macrolide resistance, we'regoing to be faced with needing other drugs, and you can see a list of potential drugsthat have been used in such patients.

the reason i'm bringing up theissue of macrolide susceptibility is because it is critical in termsof the outcome of the patient. in pulmonary disease, if you havea macrolide susceptible patient that has noncavitary disease, we expectculture conversion in 80% of the time, in more extensive diseasewith cavities, less than 50%. but in the setting of macrolide resistance, ifyou don't do surgery or give a prolonged course of iv aminoglycoside, theculture 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 givingthem 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 disseminatedmodel, we have the same question, is it macrolide susceptible or not? but we would never give intermittenttherapy in this setting. and i would strongly encouragethe use of iv amikacin. in some of these patients, theyhave received months of iv amikacin,

and that would probably be necessaryat least getting to the point that you could we hope convertthem and consider surgery. now, this is a busy slide, but i just wantto point out the outcomes in these patients. so these are 10 patientsthat were reported by kohler with chimaera infectionsrelated to heater-cooler units. and if you look at each ofthose 10 that has a red box in that second column, thoseare patients that died. many of these patients had to have repeatsurgery, in some cases multiple surgeries. so the outcome, despite starting insome 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 infectioninvolving foreign material, presumably covered in a biofilm. these are largely bacteriostatic drugsthat we're using to treat chimaera. and we know in other patients thatwe see low serum drug concentrations, and i think particularlyso in very ill patients. and of course, some of these -- well, all ofthese have comorbidities in terms of some form

of heart disease, and by the time they present, they may have liver disease aswell as nephritis, as noted. so this is a very difficultpatient 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 muchsooner than we've been able to do so far. so i'll stop with that, and i'llhand it over to dan, dan diekema. all right, thank you very much, chuck. my job over the next 10 minutes is to discusshow to find cases, how to communicate risk for this infection, and howto reduce risk for infection

after exposure to heater-cooler devices. so a lot of what i'll be describing comes out ofour experience at iowa after we detected a case of invasive mycobacterium chimaera in a patient who had received surgery usingcardiopulmonary bypass at our institution. once we confirmed that this patient had noother risk factors for mycobacterium chimaera, we immediately convened ourhospital emergency incident command, as we would in any significantoutbreak or potential outbreak, in order to get the right people aroundthe table to assist with case finding, to assist with a communication plan,and to assist with other aspects

of the outbreak investigation, includingreducing risks for any further exposure. within the next two weeks, we completed alab-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 thedevices outside of the operating room. so you could say it was avery busy couple of weeks. so this was back in january of this year, andat that time we were taking all of these steps

as a result of having identifieda case linked to our hospital. however, in june of this year, asyou heard earlier from dr. perz, the fda issued a safety communicationrecommending that some of these steps, including provider notification and casefinding, be performed at all institutions who use the device that has been implicatedin the invasive m chimaera outbreak, the sorin livanova 3t model, or atleast those centers who use units that were manufactured priorto september of 2014. so let's begin by discussing case finding. the cdc has excellent interim guidanceon identification of possible cases,

and that guidance is published at theurl that's at the bottom of this slide. the guidance begins with a laboratoryassessment, to find any patients that have positive cultures fornontuberculosis mycobacteria, specifically mycobacterium avium complex, withinwhich we find chimaera, from invasive samples like blood, bone marrow, or tissue samples. with this list you can proceedto a clinical assessment. do any of these patients have those clinicalmanifestations described by dr. daley? prosthetic device infection, valve, orgraft, sternotomy infection, mediastinitis, bloodstream infection, or adisseminated inflammatory process,

specifically a disseminatedgranulomatous inflammatory process. which many of these patients have. finally, when you have patients that areidentified by this lab in clinical assessment, they should have an exposure assessment. do they in fact have history ofexposure to cardiopulmonary bypass? now, there are some limitations to thiscase finding approach that should be noted. first, we really don't have enoughinformation yet from the global outbreak to know how far back to gowith the laboratory look-back. everyone agrees that it shouldbe at least four years,

but clearly there have now beencases 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 arerelatively 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 whenrecognized risk factors are present, like aids with a low cd4 count, orother very severe immunocompromise. prior exposure to cardiopulmonary bypass in an otherwise immunocompetent host wasreally only recently recognized to be

such a risk factor based upon this outbreak. and that is still not widelyunderstood by clinicians. so it's very important to understand thatactive case finding is also required. now, the cdc guidance does addressthis by noting that afb cultures or mycobacterial cultures should beobtained in patients who are exposed to heater-cooler devices, who meet theclinical criteria that were described earlier, prosthetic, graft infection,endocarditis, etcetera. but also who have some of the generalsymptoms listed here on this slide. persistent fever of unknownetiology, night sweats,

joint or muscle pains, weight loss, and fatigue. the guidance also suggests sending anymycobacterium avium complex isolates that are detected to a referencelaboratory for species level identification. as dr. daley mentioned, most hospitallaboratories, even those that do a lot of mycobacterial work, do not do the sequencingrequired to differentiate the different species within the mycobacterium avium complex. so a couple of practical approaches we've alsotaken here for case finding, recognize the fact that many of these patients have beenmisdiagnosed as having sarcoidosis due to the histopathology findings ofnoncaseating granulomas in various organs.

so an existing diagnosis of sarcoid in apreviously exposed patient is also an indication to consider afb cultures,similarly for a diagnosis of culture negative prostheticvalve endocarditis. we've also developed a best practice alert,or bpa, for our electronic medical record. this bpa fires for any patientwho has had cardiopulmonary bypass and also has a diagnosis code for a febrileillness or who has fevers without known cause. the bpa includes in its instructionson how to order afb blood cultures, and includes instructions onhow to order an id consult. now, for our patient notification, we usebilling codes and or logs to develop a list

of all those who are exposed to a heater-coolerdevice, although those at highest risk for disseminated disease clearly arethose with prosthetic valves or grafts. we decided to notify allpatients who are exposed, including some who had the deviceon standby during the procedure. our perfusionist told us that sometimes thosedevices were running even though they didn't end up having to be used. we decided to require a patient response toensure that all had received notification and used a toll-free line staffed by an rn witha script and an algorithm that we had developed. we called those who didn't respond tothe letter within a set period of time.

if the exposed individual who called inor who we connected with had symptoms, they were given the option to be evaluatedin an ntm clinic or mycobacterial clinic that we had set up for thispurpose, or to take the information from the letter we had sentto their personal physician. this is just an excerpt from the patient letter. these letters were reviewed quicklyfor plain language and also translated into the preferred language of the patient. we also had translators onlineavailable for the 24/7 call line. importantly, we also sent lettersto all of our referring providers,

because many patients post cardiothoracicsurgery will get their follow-up locally. it included a detailed questionand answer about the issue. and i should really add, ishould have added this earlier, our colleagues at wellspan healthcaresystem in york, pennsylvania, other colleagues who had dealt withthis, 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 soonas we were sure that most patients

and providers had received theletters so that they didn't hear about this issue first from the evening news. we also, of course, designated asmall 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 thetime we did the notifications. which includes the information we wanted toshare with patients, providers, and the public, as well as links to cdc and fda materials. the clinic we set up for patient evaluationwas staffed by a physician's assistant,

with an id physician on siteas well for consultation. we developed a checklist to help determine whencultures should be obtained, updated our policy for afb blood culture collection, and we had to order additional blood culture bottlesspecifically for the afb blood cultures. which brings up lab capacity, which ithink is a very big issue for your hospital if you're dealing with this situation. very few hospitals have full servicemycobacteriology laboratories. even in labs like ours that do a fair bit ofmycobacteriology, most still send isolates out for a complete species levelidentification and for susceptibility testing.

so you need to involve your lab directorvery early to help with questions about your capacity, for doing additionalcultures, the need for send-outs, what laboratory you will beusing for your send-outs. in our case the initial evaluation, whichincluded afb blood cultures on close to 200 patients, exceeded the capacity ofour instruments, so we did have to switch over to a manual method for afbculturing, the so-called isolator method, for a time during the initial aftermath. so very important to get yourlaboratory 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 inthe heater-cooler water circuits. we sent those organisms to national jewish alongwith patient isolates for genome sequencing, to confirm genetic relatednessbetween the isolates from the heater-cooler unit and the patient. we also reviewed, of course, our cleaningand disinfection protocols to ensure that we had been meeting or exceeding all ofthe current manufacturer's instructions for use. and then we developed or had ourengineering team develop these pass-throughs, which was basically drilling a hole inthe operating room wall and putting these,

what are illustrated here, spacesthrough which the tubing could pass, so that our heater-cooler devices couldbe operated outside of the operating room, with the or maintaining positive pressure. which we felt would eliminatethe ongoing risks to patients. now, additional engineering solutionsobviously are needed to ensure separation of heater-cooler device exhausts from or air since not all operating room suitesare have a configuration that makes it simple to remove the heater-cooler devices from the or. so in summary, this outbreak presents severalimportant challenges for case finding,

for communication, and for risk mitigation. for case finding, as i've mentioned, manypatients receive their follow-up care locally, not where their surgery was performed. symptoms are often quite nonspecific. and mycobacterial culturesare not routinely performed. thus, i think it's almost a certainty that manyof these cases are currently going unrecognized. for communication, we are stillfairly early on in this outbreak. so there a lot of unknowns, unknownsabout the degree of risk after exposure, about variables that areassociated with increased risk,

how to manage the infections once they'rediagnosed, and how to improve outcomes that to this point, as dr. daley alluded to, really unacceptably high crude mortalityrates of 50% or greater currently. our risk mitigation is also complicated. once colonized with nontuberculosismycobacteria, heater-cooler devices are extremelydifficult if not impossible to decolonize. i've yet to see a disinfection methodthat's been reliably proven to be effective. water cultures are also of questionablevalue, as many labs don't do them well. there's only a small number of labsi think that are good at doing them.

and we're using one of those labs. but even so, we find that cultures flip backand forth between positive and negative. and as chuck mentioned, theytake eight weeks to come back, so they're not immediately actionable. finally, it seems clear that weneed to try to achieve this goal of separating heater-cooler unitexhausts from operating room air, but there aren't simple solutionsavailable at this time to do so. while we were able to move our unitsoutside of the or, clearly from discussion with colleagues, this isnot possible everywhere.

at a minimum, the fda, as dr. perz alluded to,recommends directing the exhaust away from the or field, preferably towardsthe or exhaust vent. but complete elimination of risk isgoing to require redesign devices that do not produce bioaerosolsunder any circumstances if they're going to be usedin an or environment. so with that, i will passthe 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. allenis going to be able to speak. so let's give it a second andsee 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'ma cardiothoracic surgeon in kansas city, and was part of the fda panelthat met recently to explore how

to not only disseminate thisinformation, but what, from a practical standpoint,you know, surgeons can do. i think you heard really some very niceconcise talks about not only the complexity of the problem but the challenges that it faces for not only the treatingcommunity 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 usedin other operations, such as liver or even renal transplant procedures.

some of the novel ways to try toisolate these, such as we saw in iowa, aren't going to be effectivein most operating rooms simply because the structure isn'tthere to be able to do that. and ultimately, design features are going toneed to be incorporated into the equipment so you prevent any biologicalaerosolization of any fluid anywhere. as an example, we're veryconcerned in our operating room, we're not able to move our machines out. and we've actually done some unique thingsin conjunction with the manufacturer to try to isolate and cone down that exhaustfan 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 surgeonsaround the country, they would, quite honestly, have an ignorance of this problem. i think while this may have been pertinent andhad risen to a nice level in id and in some of the cdc and fda levels, somehow thisinformation just wasn't disseminated out to heart surgeons. we've been fortunate in that in workingwith the fda in an effort to try to continue to get more people involved and have abetter understanding of what this problem is.

we've got a paper that we'll be presentingat the american heart association in november and another paper at the society of thoracicsurgeons meeting in houston in january, that will at least help alert surgeonsto be on the lookout for this problem. and not just surgeons, but cardiologists. because oftentimes, the surgeon, after sixweeks, might not see their patient again, whereas a cardiologist or a medicaldoctor may be following these patients for the rest of their life. thank you, dr. allen. and i think our final summarywill come from dr. mike bell.

dr. bell? well, thank you everybody. i think that was a wonderful arrayof expert comment and insight. i just want to summarize byrecapping very quickly here. we are dealing with life-saving devices. we are not in a situation wherewe can stop using these devices. and if you look at the incidence ofthese outcomes compared with the number of successful surgeries, these remainvery helpful important devices. nonetheless, there is a potentially verylarge number of individuals exposed.

the presentation, as you all heard, is verynon-specific and potentially slow-moving. the pathogens grow slowly and havevery specific diagnostic requirements. and so tying this altogether, i think as youjust heard dr. allen say, not only surgeons but in particular those people whofollow patients after an open procedure of this sort need to maintaina high index of suspicion. anytime they're seeing a patient with a persistent infectiousseeming non-obvious process, and include cultures for acid-fast bacteria. you heard dr. diekema say that, youknow, for a systematic look-back,

this also involves partnering withthe laboratory director to make sure that the ability to do thatkind of culturing exists. but in particular, not just for look-backs butspecifically when you're looking at someone with symptoms, getting cultures foracid-fast bacteria is a very important step. otherwise, the diagnosis will not be made. lastly, i think interim solutionsfor the location of the machine, as you just heard, are not a perfect solution. some places have removed the machine toa space outside the operating theater. other places have devised containment systemsto contain the outflow of air from the machine

and direct the outflow of airaway 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 backto 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 topquestions we're getting, it actually is around the issue of cleanability. i'm wondering if maybe dr. diekemaand dr. daley want to start,

and then we'll have someof our cdc folks jump in. so dr. diekema, you talked aboutwhat happened to some of the devices that were used on these patients. but once a unit is contaminatedwith ntm, is the unit cleanable? hi. so i think that's a really it'sa good question and a difficult one. the literature that's currently outthere is not, in the clinical experience that places have had, isnot particularly reassuring. that certainly you may with sort of more aggressive cleaning disinfectionapproaches suppress the level below the level

of detection or intermittentlybe unable to detect it. but many people have had the experience ofalmost no matter what they do with these units, they eventually will findthe same the organism again. one thing that is clear because of thepropensity of these organisms to form biofilm and their extreme resistance to disinfectiononce that's happened, any attempt to eradicate from a unit would require completereplacement of all the internal tubing. so if other faculty know ofanything more recent from fda or the manufacturer, i welcome their input. this is keith allen, andi would echo those comments.

that i think once you have thebiofilm, that disinfecting that biofilm without a complete changeover of theinternal parts is going to be impossible. but i do think everybody needs to be madeaware 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 notfollowing appropriate ifu on how to take care and maintain these equipment. so i do think now within the perfusion communitythere are some very specific recommendations from all heater-cooler manufacturers on howto appropriately care for their devices.

and the goal would be to prevent biofilm by keeping these devicesup to date from the get-go. great, thank you. the next question is for dr. joe perz. dr. perz, you mentioned a couple types ofheater-cooler devices that cdc has looked at. but has cdc looked at any other heater-coolerdevices 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 receivedreports of m chimaera infections

or unit contamination withother brands and models. another follow-up questionwe're getting quite a bit is with regards to other types of infections. are we seeing any other types of infectionsassociated with these particular units? no, you know, and i don'tknow 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 reportsto indicate that that's happened.

so our next question is foreither dr. daley or dr. diekema. should healthcare providers be usingsome sort of air filtering system for the exhaust on these devices? well, from the infectioncontrol, you can have it. i think when dr. allen was talking aboutdesign modifications and engineering solutions, certainly one that would seem obviouswould be, could one filter the exhaust such that mycobacteria could not getthrough and you'd prevent this bioaerosol. i think the problem is jury-riggedsolutions that individual institutions take that have the potential tointerfere with the operation

of the heater-cooler deviceare potentially problematic. and some of these devices move so much air thati'm not sure whether or not it would be feasible to have the filter, the exhaust, withoutinterfering with the operation of the unit. so i agree that that would bepotentially a great solution. maybe others know, you know,more about the feasibility. but i think at this point, i'm not awareof 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 thatthe exhaust is somehow routed out of the or without mixing with the or air.

but i'm not aware of anyone that'sslapped a hepa filter on the unit. this is chuck dailey. can i just, there was a piece of thatthat was about healthcare workers. so a healthcare worker -- and i waslooking at some of the questions. so healthcare workers should notbe at very much risk from chimaera. i mean, it's -- we don't know of anyhealthcare workers who have been affected by these organisms working in the ors. so remember it's a fairly low virulentbug 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 mainconcern are the patients. one of the things, this is keithallen again, and one of the issues that with redirecting flow evenoutside the operating room, the reason that we see these infectionsparticularly on prosthetic materials is probably because while the prosthetic material is sittingon the back table waiting to be implanted, you have this aerosolized bioproduct driftingdown onto the backfield that then lands on the device, and then it'ssubsequently implanted. so redirecting it, while it may be anidea to get it out of the operating room,

redirecting it to other areas of thehospital, particularly where surgical products or supplies are stored or otherequipment 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 educationfor this webinar, you must complete and pass the post-test activity at 80%. a pop-up window post-meeting survey willappear when you close out of your webinar.

the link to the ce post-test andevaluation is included in this page. if you happen to miss the pop-uppage, you can access this information from a link we will send you viaan email following today's webinar. with that, i'd like to thank our speakerstoday for a very lively discussion. and thank you for all that youare doing to protect patients. thanks.