us on a Sunday morning at 9 a.m. local time. Welcome also to those who are streaming in. I understand that at least about a third of the participants are online virtually. My name is Dr. Ken Castro. I am professor of global health epidemiology and infectious diseases at Emory University and before that I was at CDC for 31 years of my life and served as director of the Division of Tuberculosis Elimination. In this session we will be covering the impact of COVID- 19 on tuberculosis from different perspectives. I'm going to start talking about the global perspective and other speakers will be covering other aspects. For the sake of clarity this is session number 106 Imperial Ballroom B. If I may have the first slide please. Oh it looks like it's there but it's not projecting over here. No conflicts of interest. I do disclose that I receive partial salary support through an Intergovernmental Personnel Act award with USAID. However all that I say here reflect my views and not the policies of that agency. For starters the outline is to cover the impact of COVID-19 on tuberculosis by relying on the World Health Organization's 2021 global TB report looking at a survey conducted by USAID in 23 high-burden countries that have bilateral agreements and then touch on a systematic review conducted by McQuaid and colleagues and published late in 2021. The other thing I will do is draw some parallels and differences as well as mutual lessons that could be gleaned of these two pathogens and look into the crystal ball about future opportunities. There's a bit of a delay in here. So the estimated global incidence of tuberculosis in the year 2020 was about 10 million persons. Shown in this map of the world are eight countries in these bubbles with names that accounted for two-thirds of all tuberculosis cases. India as a country accounts for one in every four tuberculosis cases. Other countries listed here are Nigeria, South Africa, Pakistan, Indonesia, Philippines, Bangladesh and China. The first thing that we observed was that when you compare the persons reported with tuberculosis in 2019 compared to the year 2020 there was an 18% decrease in the incidence of tuberculosis from 7.1 million reported to 5.8 million reported and conversely deaths increased by a hundred thousand during that same time interval from a total of 1.41 million to 1.51 million deaths. In the field of tuberculosis as you saw we estimate a global burden of an incidence of 10 million yet a fraction of them are reported. So we refer to those as the missing TB cases because these are people who are not reported and we have no idea of what's going on in terms of their outcomes. What you'll see from this slide is that in the year 2019 there were 3 million notified cases and that increased to 4.2 in 2020 and potential causes include under-reporting of detected TB cases especially in countries that rely heavily on the private sector for reporting and diagnosing and treating people with tuberculosis. Overestimation of the TB incidence by medical models but I'd be delighted to talk with you later if you have any questions about how estimates are arrived at by the World Health Organization. Under diagnosis of people with tuberculosis and service disruptions due to the COVID-19 mitigation measures and shutdowns I mean I work in Atlanta at the Grady infectious diseases program clinic and we told all our outpatients don't show up if you're doing well if you're virologically suppressed we will give you renewal of your prescriptions but stay away we don't want you to get infected with SARS-CoV-2. Another source of data is the Global Fund for HIV, tuberculosis and malaria and in their Global Fund report of 2021 they showed how all three diseases under their purview were severely impacted but the most severely impacted of the three is tuberculosis. So I've already mentioned the decrease in tuberculosis reported cases there was a 19% increase in the number of people with multi drug resistant tuberculosis and paradoxically in children there was an increase of 13% who were identified as contacts and started on tuberculosis preventive therapy which is one of the targets and what you're going to hear some more about during this morning. I'm now moving to the quick survey that was conducted by USAID of the 23 high burden countries with bilateral agreements for tuberculosis. 83% of those countries reported deployment and repurposing of health care workers from the TB programs to respond to COVID. I'm sure you've all been part of that yourselves. Treatment of hospitalized patients with multi drug resistant TB, 57% of countries reported a reduction in the number of beds available for people with MDR TB because they were being used for people who required treatment for COVID-19 especially in the early phases where they required supplemental oxygen intubation and intensive care unit type management. And then to add insult to injury and 52% of the countries the TB budget was repurposed to COVID-19. I was personally engaged in a survey that was planned in Botswana for a national TB prevalence and we had purchased all the equipment all the gene expert tools and in March of 2020 I was told Ken this is not happening the budget is being used for the COVID response. So that gives you a very tangible example of what was going on. In addition gene expert equipment shown at the top right hand side of the slide is a module where you can put these cartridges to establish the diagnosis of tuberculosis using PCR methods. As you can see in the bottom there's a cartridge for M tuberculosis and there's also a cartridge for SARS-CoV-2. And we saw that in half of the countries which responded to the survey in 11 to 25 percent of them the gene cartridge machines were repurposed for COVID diagnosis and that included countries such as Mozambique, Myanmar and Zimbabwe. In 6 to 10 percent Afghanistan, Bangladesh and Zambia the machinery was repurposed and in less than 5 percent of them they were repurposed and those included the countries of Malawi, Democratic Republic of Congo, Nigeria, Uganda and Philippines. In that same survey the percent change in TB case reporting in 12 countries as shown in these. So you see two countries reporting a 10 percent drop in TB case notification and other five countries with a drop of 10 to 25 percent and in red countries which experienced a larger than 25 percent drop in TB case reporting or notification. In one setting in the country of India they proactively established a bilateral or simultaneous diagnostic testing for COVID-19 and tuberculosis and I think it's one of the most powerful lessons where people who came in with respiratory symptoms at the left of the algorithm with TB were also tested for COVID-19 and depending on the response then that guided the proper management of these patients. Conversely if a person showed up tested for COVID-19 they were also simultaneously tested for TB. As please recall that this is a country with highest incidence of tuberculosis in the world and based on the result they would do a chest radiograph and guide treatment and this example has been replicated in many other countries that have a high burden of tuberculosis. Sadly when they were hit by the Delta wave in late 2020 things were not running as smoothly as they did in the early phases of the pandemic. This is the the data review that was provided by McQuaid. You're going to have access to the slides as well as to the source of information. Using the tuberculosis treatment cascade that looks at the people with TB infection then who's treated and what the outcome is and it's a very busy slide. I don't expect you to read it in detail take a look at it subsequently but at the right hand side I've listed the increases in TB cases are anticipated when you have a shutdown and there's household contacts who are going to become infected. There are going to be delays in testing and treatment, treatment interruptions, lower TB preventive therapy coverage or TPT, lower coverage of BCG vaccine which is used universally throughout the world at birth for children to reduce the risk of meningitis and disseminated tuberculosis with an 80% efficacy for those. Decreases in TB cases would be anticipated if there were fewer community contacts. Mask wearing might have a beneficial effect but that still needs to be seen. Low demand for testing and treatment would give you an artificial reduction in TB cases as well as lower enrollment in TB treatment as monitored by programs. So having done this review just as a reminder there was an increase in the number of deaths in tuberculosis globally, fewer people were diagnosed with TB and many of the resources were repurposed for the COVID response. I'm now going to share with you the parallels and differences using a framework in a perspective that we published in Emerging Infectious Diseases and I'm going to go into details that don't appear in that perspective using a couple of tables to illustrate these points. Seems to be a delay here with the remote control but here we are. So this busy table shows the parallels looking at M tuberculosis and SARS-CoV-2. Both are airborne transmission by droplet nuclei. Sadly for many of us it took a while for the world to come to grips with this reality. I think we spent too much time washing our hands and desanitizing rather than paying attention to aerosol transmission of SARS-CoV-2. Transmission by contaminated surfaces and fomites is almost never seen in tuberculosis but it has happened. We've seen rare case reports where someone irrigating an abscess that generated aerosols that splattered into the eyes and mucosal surfaces became infected with M tuberculosis. The asymptomatic phase is present in both and in fact in the case of tuberculosis we have learned through more than 25 national TB prevalence surveys that look at population-based sampling, household visits, people are questioned about signs and symptoms, everyone gets a chest x-ray if positive they get tested for M tuberculosis. We have seen that as many as 50 to 70 percent of people with bacteriologically confirmed tuberculosis deny having weight loss, fever, cough or any of the symptoms that we asked for in these surveys. Maybe the way we ask the questions are inadequate but the reality is that they seem to have a paucity of symptoms that in turn results in them not seeking medical care for tuberculosis. The asymptomatic phase for COVID-19 is well known. Respiratory disease is a predominant in the world over two-thirds of tuberculosis cases are pulmonary and the other fraction is extra pulmonary in nature. We have seen also how SARS-CoV-2 primarily affects the lung but not exclusively and we've been learning constantly about this since the pandemic began in 2020. Case finding relies on rapid molecular tests for both conditions. I showed you the GeneXpert cartridge nucleic acid amplification test is used. Cough type investigations is a key component of tuberculosis prevention control and certainly in the case of COVID where it's been called contact tracing rather than contact investigations. Isolation during the infectious phase ideally accompanied by psychosocial support is used for both conditions and in fact if you look at many of the statutes in different state health departments that rely on isolation and quarantine they stem from the experience in tuberculosis and we've needed to adapt them to the reality of COVID. Both conditions we've learned are severely impacted by social determinants of health and prevention by administrative engineering, ventilation and personal respiratory protection is quite relevant and important for both conditions. I'm going to now pay attention to some of the differences. First the incubation period for tuberculosis leading to disease is prolonged. It takes about 2 to 12 weeks to develop a positive skin test or interferon gamma release assay and about 3 to 9 months to develop tuberculosis if you have rapidly progressive disease. In the case of SARS the incubation period is very short. In fact I'm being generous when I use the upper range of 14 days. The duration of exposure for infection to occur we have learned that in tuberculosis it takes longer probably more than 8 hours or days whereas in the case of SARS-CoV-2 it could be as short as 15 minutes of exposure. We have vaccines for both 101 year old vaccine BCG. I mentioned the efficacy of BCG to protect infants against meningeal and disseminated disease. The systematic reviews show that the efficacy of BCG in protecting adults ranges between 30 and 66 percent and it's not considered a reliable protection or durable protection. If you look at the various vaccines that were initially approved under emergency use authorization, some of them have received further approval at FDA, highly protective against hospitalizations and death. The treatment of course varies. It's prolonged. In the case of tuberculosis for those of you who don't know or are not familiar with the TB jargon, we use H to abbreviate isoniazid, R to abbreviate rifampicin, Z to abbreviate parazitamide and E to abbreviate ethambutol. So it's a six months regimen. More recently clinical trials have demonstrated that you can use a short shorter four-month regimen of isoniazid, rifapentine abbreviated as a P, parazitamide and moxifloxacin and there's a six-month regimen for people with extensively drug-resistant TB or multi drug-resistant TB refractory to treatment with the other drugs and B is a betaquiline, P is pertonamide and L is lonezolid. At the right-hand side I've shown you the antivirals of injectables and oral antivirals for COVID as well as the monoclonal antibodies and of course I'm not doing justice to the more recent ones that have shown up. Active surveillance for tuberculosis is embarrassingly slow. I'm showing you data for 2020. The data for 2021 have not yet been released by WHO and we're getting a daily ticker tape approach for COVID-19 and I think this is another important lesson that we need to adapt to tuberculosis. Universal genotyping is available for tuberculosis in the United States but it's not routinely used elsewhere in the world and in the case of COVID-19 we've relied on routine surveillance to know what variants there are and it's what's giving us this daily information. Preventive therapy is also available for both conditions. More recent preventive regimens include three months of isoniazid and rifapentin for tuberculosis given once weekly for a total of 12 doses. That's the one lower down abbreviated as 3HP12, four months of rifampicin or one month of isoniazid and rifapentin studied in HIV infected persons and hasn't been recommended yet outside that group. In the case of COVID we've used monoclonal antibodies as well as oral antivirals in the early phases for contacts at high risk of bad outcomes. So now moving from here let me share with you our perspective and observations in outbreak investigations. There's a very rich history as well as publications in the case of tuberculosis. I'm showing in these busy slides two diagrams of a big outbreak of tuberculosis in a naval ship USS Bird around 1965 where one of the crew members developed tuberculosis. It took about six months to establish the diagnosis since the symptoms developed and shown in here are diagrammatic representations of the birthing in the three layers. If you read the study they say we don't replicate it for security reasons but want to give you an idea. There were at the end seven persons with active tuberculosis and more than 45.5% of the 308 crew members had new latent TB infection. The Navy used to conduct and I think they still do at entry routine tuberculosis skin testing and all these persons were shown to have converted from a negative to a positive to break in a skin test. Furthermore in the adjacent compartments and shown in these little dots in these diagrams are the ventilation patterns and they showed that there's almost a dose response that was experienced in the proximal birthing spaces where the crew members were and there's about eight diagrams that I'm not showing here where others were less likely to become infected if they were further away and not sharing recirculated air. On the right hand side there's an aircraft where in the late 1990s we documented TB transmission and you can see the careful detail of the seating accommodations and a better understanding of ventilation. At the lower right hand side I show the heavy use of social networks that has been increasingly used in tuberculosis to understand transmission. If we look at the investigations for COVID outbreaks I was pleasantly surprised and impressed by the cluster outbreak investigation the one through restaurant which included an assessment of seating proximity and ventilation system and these are the maps shown in here with the arrow showing ventilation the tables where the index case was seated and others who became infected with COVID. However when you look at other published COVID outbreak investigations they lack the systematic application of environmental assessment and proximity assessment. I've read and kept looking for these data in the assessment of the USS Theodore Roosevelt COVID-19 in the President's Diamond cruise ship. The reports tell you how many people were infected but they give you no idea of where they were seated, what was the ventilation system and I think this is a loss in our ability to better understand transmission dynamics. Same thing has been absent in long-term care facilities which at one point in the United States accounted for 6% of total COVID cases and 38% of deaths. We've also seen in schools and camps and again I think it's it lacks that nuanced investigative approach. So enough of my criticism of these outbreaks look at some of the other things that we can learn. COVID-19 has taught us the use of information technology. In fact as I arrived in Utah I was prompted to sign up do you want to be part of the Utah Department of Health notification of COVID exposure and in this list we see how many countries of the world have implemented the use of information technology apps to better understand contact tracing, case notification and that's what's shown in the bar graphs in there. The list is long, it shows you the application, the purpose of it and who's producing it and it's something that we can do better in tuberculosis. So I think that these are mutual lessons that go in both directions. So I'm going to give you a summary now. It's clear that the disruption of services resulted in a global 18% decrease in TB case detection accompanied by 100,000 increased mortality. Implementation of bilateral testing did facilitate simultaneous testing for COVID-19 and tuberculosis. I think in the future we need to do better for other airborne pathogens ideally relying on multiplex assays for diagnostic platforms. We should emulate COVID-19 surveillance to conduct active TB surveillance, provide adequate human resources with expertise in contact tracing and investigations using digital technology and use of virtual monitoring of patient-centered adherence, implement infection control prevention measures as well, assess the role of engineering ventilation control, ensure heightened political will and balance and leverage preparedness and response for future pandemics with accelerated progress to end tuberculosis. And I realize that I've gone way over time having spent some time with those tables, but we will be open to questions maybe. I don't know, Julie, if you want to do them now or later. Now? We need to move on. We will. Please write down your questions. We'll get back to them. Thank you for your attention. Okay, so I am Dr. Julie Higashi and I am the director of the TB control program in Los Angeles County. I am also the representative from the National TB Controllers Association and I have to say it's my very great pleasure to be here and one of the joys actually of the pandemic era that I got to work with ACOM on the healthcare personnel testing guidelines. So I just want to say thank you for helping make COVID-19 for me a little bit brighter. So I'm still waiting for my slides, but in the meantime, I just want to share that I'm supposed to be talking about the domestic perspective for TB. And since we're working on our timing, I'm just going to launch in to say that really the domestic TB epi situation really reflects what Dr. Castro just relayed, which is a sort of a sustained decline in TB disease incidents pre-COVID that had plateaued and then a remarkable reduction in 2020 of about 20% declination in disease incidents. We saw in 2021 a modest recovery of about 2 to 3% and those are really thought to be secondary to global migration, not just immigration, but many of our citizens do enjoy bi-national life and with that reduction in travel, we did see a big impact on disease incidents. The other factors really also related to the pandemic have to do with reduced capacity for TB program activities. So as Dr. Castro relayed, diversion of staff was a reduction in the ability to do things like contact tracing. It's a lot easier to talk about TB now than it was pre-COVID because everybody knows what air transmission is, airborne transmission is, and everybody knows what contact tracing is. But in L.A. County, we had a 50% reduction in capacity to see patients in our clinics and also to do the contact investigations. So we know that we weren't out there detecting TB disease incidents. So it was kind of remarkable to see that the number of children at a global level increased despite all of these, despite, you know, all the reductions in diversion of staffing. I think that we won't be able to really know for a number of years the impact on healthcare delivery and the disruption for COVID-19. Inpatient hospital beds were near and dear in L.A. County. We couldn't get patients who were literally dying from their TB admitted to hospitals. They just, there were just no beds. Our inpatient TB unit was diverted to respond to COVID-19 and we haven't recovered that unit because the decision was made to continue using that unit for other purposes. So these are the types of impacts that happened to COVID-19. People weren't getting ambulatory care. HIV AIDS delivery was being done by telemedicine and as you might, you know, guess that's not the population that you can really do telemedicine with very easily at times. And so now we're seeing the impact of AIDS TB, you know, just people not getting access to their ARVs. And so that healthcare delivery, ambulatory access, also had an impact on disease incidents. So I still don't, I don't still have my slides. They are up there. Oh. Is it? Ah. Whoops. Okay. So I'm going to just, I guess I'll just keep talking. I don't know. They said my slides were there. So I'll just keep talking. So from the standpoint of delay diagnosis, I think delays in diagnosis, I think that is another factor. And in terms of domestic TB data, the evidence of the delay diagnosis being a factor in 2021, the percent of smear positive TB cases reported amongst non-U.S. born disease incidents increased slightly, suggesting slightly advanced disease. And the other factor was that increase in reactivation TB in folks who had been non-U.S. born individuals who had been in the United States for over 20 years. So I really think that, you know, it's too early to tell. We hope that this decline we can keep, you know, reduced relative to pre-COVID, but my sense is we're going to be seeing, and what I'm seeing in L.A. County right now, is a return to baseline as far as disease evaluations and about 20 to 30% increase in confirmations relative to the previous year. So I think that's going to be important. The other factor here that I don't think we really have the data on yet is the impact of COVID-19 on death. And in the Spanish flu epidemic, it actually accelerated TB elimination because it killed the future disease incidents before they happened. And so there's folks that actually died from COVID before their TB was diagnosed, but there are people who might have just been on the cusp of progressing to TB, and I think it's going to take us a while to figure that story out. So I think that's the epidemiology. And I'm trying to think. I think from what the other, the next slide I have has to do with the LTBI campaign because CDC, having done this analysis, really has said, how are we going to recover from the epidemic, from the progress that we've lost on the progress toward TB elimination because of COVID? And the way that we're going to recover is to double down on TB elimination. And so what is that? And the definition of TB elimination is about one per 1 million case rate in the US, and we're sitting now around between two and three per 100,000. And so what that means is that we need to actually go out and look for TB infection and TB disease. And TB infection is the form of TB that is not contagious. About 90% of people who are exposed to TB and get infected will not ever progress to TB disease. But we don't have good biomarkers or ways of understanding who's going to progress. So essentially, anybody who has LTBI or latent TB infection is on opportunity prevention and for providing or treating that LTBI so that they don't become a future disease incident. So as far as exposures are concerned, not everybody who's exposed to TB gets TB infection. And the way that we define that from an occupational perspective, you have to have a cutoff as far as a certain number of hours. And that's pretty variable across the United States. So that's something that's going to be determined by your local TB program or your state program. And so it's an important distinction to make because it really defines the pool of people that you're going to want to be able to offer testing and treatment to once there has been an exposure. And so in Los Angeles County, that cut off for us is eight cumulative hours within one week. That's what we consider a significant exposure in order to name somebody as a TB contact. About 10% of people who do get infection progress to TB disease. Half of them progress immediately to TB disease. And the other half reactivate. And that reactivation is going to be dependent upon comorbidities, et cetera. People who get TB disease, about 10% of them die with their disease. It's very, very treatable. But from the standpoint of what COVID did to that recovery rate, it did increase morbidity. And so if you had coincident TB disease, these are LA County numbers or actually California numbers. If you had coincident TB disease and COVID, then your risk of death was four times that of somebody with just TB alone. And that's already 10%. So it was very morbid and something that we're going to continue to track. These are pre-vaccine numbers. And so we hope that we're going to have improvement in that. So right now the CDC has got an LTBI campaign that's ongoing. And it is really directed at Asian Pacific Islanders and focused in the western region, particularly in Seattle and Los Angeles. And focused on the Vietnamese and Filipino population. It's called the Think, Test, Treat TB campaign. And there are a lot of nice materials. There's some language resources for these populations. Moving on to thinking about sectors that really think about TB testing. And in the United States, I think it varies across states and local municipalities. And for the most part, I think you're familiar with healthcare personnel, correctional personnel, people who provide in-home services get routinely tested on hire. People in educational settings are tested. I'm going to just check to see if we're making progress here. Nope. Okay. I'm not going to have any slides. So do you want me to just keep going? Or? Okay. All right. I do. You know what? Let me just try to share some thoughts. But that's kind of, that's unfortunate. Okay. So I said, so basic sort of sectors have to do with education, in-home care, correctional, and also providing services to homeless populations. So those are the factors. As far as, you know, TB, TB 101 on working after you've had an exposure. And I don't know how many of you've had a TB exposure happen on your work site. For a show of hands, can I see if any of you have that? Okay. so you've all had that experience. And I think the most important thing once you've got wind of this is to reach out to your local health program and confirm that an exposure actually happens. I can't tell you about eight times out of 10. That's not gonna be an exposure. It's gonna be somebody with TB infection. So you can then dial down the anxiety by 100% once you confirm that you really didn't have an exposure. So just pick up the phone. The people on the other end, they want to hear from you and they will talk to you. There's a situation coming from an occupational health provider. You will get through, there will be a person to talk to you. So that's the biggest piece. And then to also make sure that you consider that they are there to help you. They are your technical support. And if you really have had a post, you know, an exposure, we are resourced to investigate after an exposure. What that's gonna look like is gonna be a little bit different in different places. And what I'm gonna talk about are some of the experiences in Arkansas and Tennessee with the poultry industry. Because this is not your typical situation. And so in those situations, communities have a large number of residents that are going to be employed by poultry factories or poultry plants. And generally they don't necessarily include TB testing on hire. But in those communities, the risk of a TB disease incident is high. So for example, there's published literature in Delaware where the case rate in the population of poultry workers was about 83 per 100,000 versus Delaware's case rate, which was seven per 100,000. And so they found over about a 10 year period that 50% of their TB disease incidents came in fact from the community that were employees at these poultry plants. There actually wasn't transmission at the poultry plants. It was just the group of people who were employed by the poultry plants tended to have a high TB disease incidence rate. So going back to Tennessee and Arkansas, in Arkansas there's a Marshallese population of 15,000 people. And 80% of the adults in that population, they find employment at the poultry plant. And there have been about 200 disease incidents, actually 130 or so disease incidents in this population in Arkansas. So what has been happening in Arkansas is it's been a slow collaboration. And usually, and what both Tennessee and Arkansas said, usually corporate really doesn't wanna engage with public health. They're worried that public health is gonna shut them down because of immigration issues or they're worried that public health's gonna bring in avian flu or maybe that's an excuse not to engage with public health. There may be a number of factors. But what these programs have done is they've been working very hard with the occupational partners on the other end. They're usually able to get buy-in. Some of the time they're not able to do onsite testing. And I would say onsite testing is your best way to resolve a TB exposure situation quickly. It's to allow the public health folks, if you have issues with avian flu, just work with them. They know what to do with PPE. They know infection prevention. But if you can get them onsite to help you with your testing and set things up, that's gonna be better for you in the end. So when these collaborations happen, we're able to really get people socialized to the idea that public health people, our primary concern is disease control. We are not going to be focusing on immigration status. And that's something both the corporate and both the employees, the staff need to understand. And over time, once they interact with us, they get that. So those are opportunities for collaboration. Who does what is really up to the health department. Ah, thank you. Okay, I'm gonna just kind of, in the interest of time. This is where I am with the models of coordination. That's just about the Marshallese population. This is where I am. But honestly, one of the most important things that you're gonna wanna consider is the ventilation. I think everybody knows how important air quality is now. And so when there's good ventilation, even in the context of contact investigations, at least in the situation of one exposure, no evidence of transmission amongst 40 contacts. So we're not talking about, sometimes it's not even hundreds of people, it's dozens of people. And making sure that contact investigation gets done is the most important thing. So this is an example of a collaboration that occurred over time in Delaware and was published. And honestly, this is a wonderful example of coordination where the health department worked with a series of poultry plants, and five or six opted in. And essentially, these poultry plants, as a condition of hire, needed clearance for the employees by the health department. And so the health department supplied support for actually the medical evaluation, the chest X-ray, and the medication. And the industry, occupational health side, supplied the access of the employees, the time to go get the evaluation. They actually did directly observed therapy. And tracked that the employees were getting the medication. And that alone was able to have the health department review treatment, and just sign off on LTBI treatment. So typically, in a population of 6,000 workers over three years, about 400 people average were identified for evaluation. 300 met criteria for needing treatment. And the completion numbers were very, very respectable from the standpoint of, this is a nine-month, probably isoniazid-based regimen. 90% initiated treatment, and then about 50 to 70% completed. So nice example, and we're talking about hundreds of people. And you're probably preventing future cases of TB from treating those people. I'm gonna try to move things along and talk about gambling casino exposures. This is my personal experience. And this is really interesting, because Werner Hudson is sitting here, and I met him when I was a TB controller in Santa Clara County. And this is an outbreak that happened in a gambling casino in Santa Clara County. It involves, and this was the largest outbreak in 2010 in California. Nine patrons and four employees in a casino. This casino also had measles exposure. I think casinos are places where people spend a lot of time close to each other, eating and drinking. And there are a lot of people who are at risk. And so we had, some of the patrons had HIV AIDS. They were on immunosuppression, and they developed TB from this exposure. Index case was treated in 2008. And this is no joke. I was on the plane. I got an email, and the index case is in L.A. County having relapsed. And now I have to figure out if it's a relapse or a new infection. But I mean, these are things that get burned into your mind. I recognize the index case's name, and I was the treating clinician in Santa Clara County for this gentleman. And so it just shows how we have to be vigilant. And because we have the benefit of whole genome sequencing, we now can track these events years later. And I had a heck of a time getting any line lists from this casino to do employee testing and patron testing. And I have a feeling that a number, there were a few more patrons that were identified after I left Santa Clara County due to the whole genome sequencing, being able to link them to that outbreak. We did have another outbreak in a gambling casino during the COVID pandemic. It actually started in 2019, but it was identified in 2020. This affected five employees, again involved people who were immunocompromised. And they were in all different parts of the casino, just sort of operations in the kitchen, also serving in the rooms, going back and forth. There was a supervisor involved. The contact investigation was delayed by six months because the casino shut down, understandably. And disgruntled employees didn't want to follow up once we got a line list because they had been laid off. We are only now actually closing this investigation after a lot of efforts. And I think we've managed to contact and evaluate about 60% of the contacts. But we'll be looking at this particular outbreak and cluster in the coming years to see how things shake out. So just to wrap up, we did have similar reductions in disease incidents, but we don't necessarily understand that this represents a true reduction. And we're gonna do our best to maintain the reduction in disease. But I think the forces are pushing otherwise. We do have TB exposures occur in the workplaces every day. Coordination between public health and occupational health can support completion of contact investigations. And so the other thing is, just because workers are not evaluated on hire, it may be in your particular situation, if you have outbreak after, or exposure after exposure, in your interest to coordinate or be more proactive with your health department. And I mean, they're gonna be, like in Delaware, a large percentage end up being disease incidents. They will work with you to resource just sort of the evaluation and treatment along TB elimination lines. So I think though we in public health are really relying on personal healthcare, individual healthcare, to actually at risk assess, test and treat LTBI. We know there are gaps there. And occupational exposures and occupational health is another opportunity for us to close that gap. So I'm gonna stop here. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. And pass the mic on to Wendy. Extra gold star is really for doing that on the fly. That's really hard to do, Dr. Castro. Thank you so much, and thank you, Dr. Castro. Okay, we are behind time, and we're short of speaker. So, what do you know? Hi, everybody. I'm Dr. Tanasi Wendy. I work at the Palo Alto VA as the Chief of Occupational Health. I did many years working with Washington, D.C.'s central office for our 400,000 healthcare workers, on TB particularly, with a great shout-out to Dr. Hodgson, who got me started on this path. Where did he go? You're not Dr. Hodgson. What's that? Oh, sorry, I didn't want to shout at you. Is that better? Okay, sorry. So, okay, so Dr. Tanasi, I also work at Stanford as an associate professor at this point, and a couple weeks away from full professor, I think. So, thank you, Dr. Higashi. Dr. Berman is supposed to be your speaker now, and she is in Chicago because there were hurricanes or tornadoes or whatever kind of weather you guys have that isn't our California wildfires, and she got stranded. So, because we're quite behind in time, what I'd like to do is run through her slides super fast. They'll all be available to you. I went through her slides and made them wordier so that people could reference those later. Dr. Berman from University of Pennsylvania has a calm and lovely demeanor and a lot of stories. She has spent 31 years treating latent tuberculosis in her workforce. She knows everything about it. So, I recommend that you check on her slides after this. I'm gonna try to race through those and then get to my talk because we really want you to have time to be able to ask Dr. Castro and Higashi and myself any questions. Okay, so this is Amy's talk. This is her outline, principles, and purpose. Her goal is to talk to you about, it's a very operational discussion of how would you treat latent tuberculosis in your workplace. So, a little different than Dr. Castro doing global and Dr. Higashi doing national, and then Dr. Berman doing functional, and then I'm gonna go into outer space on mine. Okay, so she wanted to show you on this slide that the latent tuberculosis is on the left, or at least on my left, and on the right is active tuberculosis, and the point of treating latent tuberculosis in the workplace is to prevent the slide on the right. She points out that in 1994, the actual MMWR guidance was also for us to treat latent tuberculosis in the workplace. It's not new, it just wasn't really emphasized. So, when we went forward with guidance in 2019, that was a lovely combination of the National TB Controllers Association, who put this panel together, with the CDC, and we wrote the 2019 guidance for healthcare workers, we just took it and flipped it on its head a bit, and said, we've been testing and testing and testing, but we have not been emphasizing treating. And that sort of goes against the entire paradigm of medicine, right? If you're gonna test for it, you've gotta be willing to treat for it. So we really tried to emphasize treatment in this, and Dr. Hudson, who's here in the front row, and myself, with colleagues in this room, then wrote a companion document that I recommend everybody look up. That is sort of the operational guidance to the 2019 MMWR. So the 2019 MMWR is 2,000 words, of 500 of it are how did we get to doing this document. The companion document's like 20,000, so it really operationalizes testing and implementation of treatment in the workplace. That was a combination with ACOM, by the way. So National TB Controllers and ACOM. The major changes between the 2010 and 2005 MMWR with the 2019, just go through extremely quickly, are primarily in the serial screening and testing arena. So the 2019 document, and this is how I met Dr. Castro at ACET and CDC years ago. We've known for a long time as the specialists in doing annual TB testing, particularly in the healthcare worker realm, that our healthcare workers are not converting to latent tuberculosis after they are hired in the workplace. So what happens is we have the cohort of the foreign-born, and the cohort of people who spent extensive time overseas, primarily making up the population of people who have latent tuberculosis. We hire them into our workspaces, whether it's the healthcare workspace, or it's energy, or mining, or I worked with Edwards Scientific, and they're making these little heart valves. So you've got people who are working in all sorts of arenas in very closed spaces who could have latent tuberculosis. They're tested for it, but not actively being treated for it. They're not getting it once they come into the workplace, particularly in the healthcare setting, usually. So the 2019 guidance said there's no place in the healthcare arena where we recommend doing annual TB testing for healthcare workers, not based on their location, not based on the ER, or pulmonary, or ID, so that serial testing for healthcare workers was essentially struck, I'll give you a caveat on that, except in settings where there's really not the environmental controls that Dr. Castro was talking about. So if you work in public health, like Dr. Higashi, you work in a border clinic, and you don't have the appropriate environmental controls, you have a waiting room full of people who might have TB, that's a cohort where your employees could still be at risk. Otherwise, you know who in your workforce already has latent tuberculosis if you test them when they come in. So when you test them when they come in, you know they have TB. What we had been doing is annual questionnaires, of which there's a lot of data that shows that nothing really happens from those that's of use. So in the 2019, we say, once you know that they have latent TB, treat them for that. So what are the treatments? Let's go through her slides. So you can have exposure, so one of the other dangerous things that happens is occasionally you will have a workplace exposure. It's quite unusual, as I mentioned. But what is more common is that you'll have a reactivation of latent TB, as I mentioned. They came into your workforce already, five years later, they still haven't been treated, and they reactivate. New hires, who you bring on, that's a catch place. How do we treat it? We treat it with INH over many years. 130 years, well, I'm sorry. Since the 1940s, INH has been used, and that treatment was nine to 12 months. Occasionally it was six months, depending on the regimens, of daily treatment. We have much better treatments now. Rifampin-based short course regimens are the ones that are recommended. These are well-established and have minimal toxicity. Sorry, I'm kind of winging it on our slides. And the reason that we really recommend that you start treating in the workplace is that there are limited doors in the public and private sector elsewhere for people to get their treatment. Primary care doctors are not familiar with latent tuberculosis anymore. It's almost a disease of the past here, and many of them will still recommend INH. You all will be the specialists when you really understand that it's these short course treatments, including just 12 days of antibiotics, that can work just as well. Public health departments are overwhelmed, as Julie showed you, with outbreaks, especially with our new immigration issues. So I basically mentioned this already, that we should be offering it to everybody, and we want to minimize barriers to latent TB treatment. Here is a chart that we made that we put in our operational guide that I mentioned to you. It shows you the short course regimens that are recommended. And so you can pull up that JOEM article for this as well, and we made it to be something that would be easy to print and put over your desk. The short course treatment that's recommended right now is three months INH plus rifapentine. That's a once a week dosing. That means you're really down to 12 days of antibiotics to treat latent TB and prevent reactivation to active TB. That is an extraordinary, extraordinary moment in medicine. I think one of the most wonderful things I've seen, because the reservoir of all of active TB is latent TB. So now we have a 12-day antibiotic course, and we can, if we institute using, advocating and treating latent tuberculosis in the workforce, we can be the ones who eliminate this reservoir in the United States, in whatever capacity you're working, whether it's a healthcare capacity or you run grocery stores or you run departments of transportation. If you test people on hire and you either get them into care through public health for latent TB or you do it yourself, you can knock out this entire cohort that moves forward to active TB. Four months of daily rifapentine is the second one. That's for four months, as I mentioned, and a couple other short course regimens. The INH six months to nine months of treatment is no longer recommended. It's associated with hepatotoxicity and liver failure. Oh, you're so sweet, thank you. Okay, so who's at risk for progression? Who do you really want to focus on? Those with diabetes, end-stage renal disease, malignancy, malnutrition, people who recently converted. Oh, this is interesting. This is an old slide deck. I know this is an old slide deck because I worked on the slide deck before and I put Amy's picture all over it so it would look like she was talking to you. So, I'm gonna just, in the interest of time, move forward. She wanted you to know that if you do decide that you're gonna use the rifamicin-based treatments, that there are some serious and common drug interaction actions, and what it mostly is is a decreased efficacy. So oral contraceptives won't work as well, and your clients then need to know that this can happen. Antiretrovirals, the preventive PEP regimens and the HIV medications, Truvada in particular, can have decreased efficacy. Warfarin and some antidepressants, so always check with your clients before putting them on a TB regimen. You want to monitor them from symptoms. You can do serial LFTs, though it's not required with a 3-HP regimen. A lot of people are more comfortable getting a first LFT round and then doing liver function tests again somewhere along the course. But again, it's just a once-a-week regimen of these antibiotics. With this 3-HP regimen, most commonly there's some nausea associated with it, because it's kind of a big dose once a week, and sometimes some sun sensitivity. She has on here some recommendations if doses are missed. She has some cases that I wasn't going to go through, because they're her cases. I'll just tell you about mine really quickly. So the one I had that really changed my life in this way was a nurse from the Philippines in 2012 came into our facility and was quantifieron. We used the blood test positive. And she was also positive in 2013 and in 2014. In 2015, and not that surprisingly, in 2016. Because we were still testing people every year, mostly because I wanted to understand how IGRAs worked. So we were still retesting the positives. So she was positive, and maybe did or didn't do the symptom review. But by 2016, was a 50-plus-year-old woman who was tired and gaining weight and all the other things that I think some people will relate to. But it turned out she actually had activated her tuberculosis. She worked in our PACU, our post-operative unit. So she was in touch with post-operative patients. When we finally figured out about four months later, when Kaiser diagnosed her and we got the information, we did our exposure investigation. These cost millions of dollars, which is another reason you should really treat latent TB in your workplace, to prevent these kind of things. First person who was given active tuberculosis by this nurse, accidentally of course, was a heart transplant. And this was a 62-year-old man who had come in from Arizona. He had had his heart transplant at Stanford. He was with us for his first post-operative visit at Palo Alto, and he got active TB. The second was a nurse who worked with her, 24-year-old who had been started on Embryol a year before. So we knew she had her negative test right before she started Embryol. She developed active TB in that year because she was immune-compromised and exposed to this other nurse. The third was a 92-year-old veteran who died with a large pulmonary abscess in our nursing care center. He had had latent tuberculosis in the past, so we don't know if her exposure to him reactivated his TB at that point. We won't know. But it was really a dreadful occurrence, and so I can only relate to you that I really feel very strongly, as I know Dr. DeCastro and probably most people in this room do, that this is something you can do. And so what Amy wanted you to know, what Dr. Berman wanted you to know, is you can do this. You can test people on hire, and then you can give them the 12-day self-administered antibiotic treatment. It is very inexpensive. It's very safe. New England Journal 2011, I put on my version of the slides, has the reference to using the 3-HP. Right at the end of her slides, she wanted to tell you, and I know that Dr. Hudson is very involved in this, that the whole animal worker cohort, whether you're working outdoors in veterinary medicine or in forestry or husbandry, or you're working in laboratory settings, there's also some risks there. And this elephant, she wanted me to tell you, is not dead. That elephant was anesthetized. But there have been multiple cases, and Dr. Hudson's from OSHA, of employees getting tuberculosis from elephants, or more importantly, giving them to elephants that can be fatal. And so the Oregon Zoo and the Philadelphia Zoo had recent cases, and I forgot what she told me about Philadelphia. The one below is Caya in Puerto Rico. Thank you. Say it again? Caya Santiago in Puerto Rico has a colony of macaque monkeys, and the workers have to be tested for tuberculosis before they go there, because you can wipe out an entire primate colony with tuberculosis. So again, there are many ways in which helping to eliminate latent tuberculosis in our population helps not just the patients who we care for in healthcare, but all of the colleagues we work with and the animals. I'm gonna just go past this and let you please look at her slides, and then I am going to move on to mine. Partner always with public health and engage your primary care specialists as you need to. Minimize the barriers to their treatment is the main goal of Amy's talk here. And we try not to do billing. It's only a couple hundred dollars for treatment, and it's a couple million for these exposure investigations. And for the cases, we had to do case disclosures to about 1,400 veterans. All of those go through the Department of Defense. And she says if you build your program, they will come. She said, you might not have a completely full stadium. Not everybody is gonna want to get treated, but if you have the discussion with them, they may go on to their primary and decide in the next year or two. But even if you get part of the stadium, you've done a good job. Okay, thank you, Dr. Berman. Please look up those slides. She would do it. She would do a much better job. Okay, and they're gonna load the next round. Thank you all for sticking with us. Okay, me, Italian, talker, loud. Okay, here's where I'm gonna go. Okay, so Dr. Tanasi, I'm gonna talk about the future, piggybacking on what Dr. Castro said. What is possible going forward? So I have no conflicts of interest, and I'm gonna mention a lot of companies. I have no particular vested interest in any of these companies, except I think they're cool. Dr. Aghashi, thank you for showing us what's going on in the United States and our home state of California. Dr. Berman, for showing us how to operationalize TB. Dr. Castro, for showing us how the disruption in services in COVID is going to affect TB worldwide. That goes along with, as much as I love Dr. Castro, part of the downer of all of COVID, right? We have spent two years being down. We've worked so hard, haven't we? I'm so tired. I am tired of being tired. So I wanted to give a talk that was more optimistic and show you what we have done in the last two years. As Dr. Castro said, we know the bad days are coming for TB. Make no mistake, it's going to be worse because of all of these resources that were pulled. So do we have to just go back to having our community health workers go out into the field and sort of doing this like one-on-one attempted interventions that has worked but is working slowly? Or can we leapfrog with the technology that's happened in the last two years? Everything I'm going to show you is very quicker than the very long talk I had. I'm going to whip through it, but it's all things that have happened in the last two years, okay? So what can we do with TB? All right, there's a lot of different places you can intervene in the TB cascade. On the left, left, sort of the old way, there's the BCG vaccine, community health workers. On the right, as Dr. Castro mentioned, mobile support and apps. And so I have a longer talk that covers all of those. So that's interesting. I think I'm missing a slide. That's fine. Where is medicine today? It is in what they're calling the fourth industrial revolution. And this is really cool. So what do we have in medicine now? You all know this. It started with those electronic medical records that were such a burden. Well, now it's totally different, right? We have machine learning. So we're starting to teach machines by inputting data, how to recognize patterns. Move into integrating those data nodes and you get these integrated analytics. Overlay that with where you want the, what you want the outcome to be and you start to develop artificial intelligence. We have deep learning, which is where the artificial intelligence actually doesn't require people to put in the questions, but can sort of generate the questions itself. We have digital pathology now. We have big data. What do we have for TB? Oh, this is cool. So they're also calling this era the internet of bodies. And the internet of bodies is because of the wearables and the different ways that our body is now linked to this internet of medicine that we're talking about. So that your heart rate and your steps that you walk today are all feeding into big data, aren't they? You can also swallow a capsule and have your colonoscopy recorded, right? So this internet of bodies is these implantables and these wearables that are changing the way we gather data about healthcare and the way things move forward. Well, where's TB? We know it's been about 130 years with I would say four amazing steps forward in tuberculosis. But look at what we're doing in two years, okay? This is really cool. This is in a very shortened version. Right in 2020, Johnson & Johnson did a $250,000 challenge grant for MDR-TB. I know this isn't exactly what we're talking about with the workforce. This was for a multi-drug resistant TB, but I wanted to show you because it's pretty cool. These were their four winners. Two in India, one in Philippines, and one in Ukraine. And as we talked about briefly with Dr. Castro, I liked this ZMQ India one. So now you have the community health worker in the lower left-hand corner going out, but he's bringing them cell phones. And these cell phones are preloaded with apps. And he's teaching them how to use the cell phone, how to use the apps. He's giving it to the community, and the community is then passing it along. With this app, all sorts of things happen. They're calling it the Patient Active Compliance Treatment Toolkit. So the community worker teaches them and how to use it. It then also has a video, it has the video observed therapy so that people taking medicine can actually video that they're taking their TB meds at the time. That speaks right into their healthcare worker who can respond to them right there in real time. How are you feeling, Melanie? How's it going? Are you sick? Did your goat eat your pills again? We'll get you some new ones. So there's an interaction that can happen there. You can set up health consultations. If Melanie says she's sick, you can send her to the local clinic and say, let's get you into the clinic tomorrow. And they're finding that it's really driving behavioral changes. Some of it is this resource of having a tool that the rest of the community is going to rely on also. And so you've got this sort of precious interaction with medicine. Now maybe two hours walk away that you're giving to someone else in the community. So there's some community resourcing there. The second winner was this TB People Ukraine. They did an MDR-TB1 where they did that kind of intervention. So it was all made by MDR survivors. And they said, well, what were our obstacles to being treated? And so people could report in and say, I had this problem with my medicines, or there's a tree blocking the road, I can't get to the clinic. And within 24 hours, TB People Ukraine would solve the problem. They would go have someone cut the tree, they would deliver the medicines, which by the way, just to mention, you can do by drone in some places now. So I don't have a slide on that. But I wanted to tell you this because we know that Ukraine is a terrible problem with cericulosis and MDR-TB. We're now having a diaspora, aren't we? All that MDR is spreading all over the world. It's going to be an issue for every one of us. All of you who hire people are going to have people who have been touched by the Ukrainian immigrants or emigrants. So when I went to the slide, when I went to the website right before I spoke for World TB Day. Sorry. It gets me every time. This is the screen that you see. It kills me. So when I saw that screen, I thought they were asking for help. But they weren't. When you look at the words on the screen, and I encourage any of you to look at it, below that it tells people what the lines are at the border and what access points are open to get out of the country. So they were actually giving help. This TB community is the most amazing group of people you can imagine. Okay. So as it spreads, and as Dr. Castro mentioned, we know everything about COVID, don't we? You probably knew in the Salt Lake City airport how much COVID there was in that airport because we have all this data and we don't have it for TB, as you mentioned. We have multiple companies, Kinsa Health Weather and then Sick Weather, two different, isn't that funny? They're doing exactly the same thing. They named themselves opposite. I thought that was pretty funny. So there are these illness tracking, but more importantly for tuberculosis, predicting apps. So you can track where it is, but for tuberculosis, we could develop those hotspots instantly. We could say, this is where TB is, this is where MDR is, isolate this population, send in the community health workers, treat them, boom, lock it down. We don't do it, but we should, and we need to, because it's not that hard to do. What else is cool? Okay, I showed you the mobile phones and how everybody's using apps. We think like, wow, mobile phones, and they better have some internet. So this is the way that we used to have internet. 20 years ago, when I started working in the field, see them bringing in the satellite? Now you've got Elon Musk and SpaceX. So SpaceX has set up this network all around the world. These are just published in 2021. It's linking primarily to low-income nations. And what did they do? Bless their souls. They set up a whole internet service over Ukraine. This SpaceX, this is gonna be one of those leapfrogs that we're gonna be able to use in healthcare if we get our act together, particularly in TB. Not that I'm looking at Dr. Castro, who's one of the world leaders in it, but we do need to leapfrog this technology and get everybody the mobile apps and move forward. What else have we learned? Acoustic epidemiology. Ever heard of this? Cool. Study at a Cornell. So this is artificial intelligence. It can discriminate between coughing sounds from TB and those from other lung diseases. Published in this paper by Cornell. A study, I don't wanna take too long on it. You can look it up, but their area under the curve ended up being 94%, which is amazing. And then regarding the World Health Organization, I wanted to mention this. The automatic classification of cough audio sounds applied to symptomatic patients requiring investigation for TB can meet the WHO triage specifications for identification of patients to move on to molecular testing. Right? That's super cool. So you have coughing on an app, on your phone that you wear in your pocket. Okay. Oh yeah, the slides are a little messed up. This is a promising, viable, low cost, easily deployable frontline screening for TB, which can benefit especially developing countries. This is the app I'm talking about. Peter Small left the Gates Foundation. He had come from Stanford. He left Gates and TB to work for this company. So this is actually one of those apps. I don't even know how you say it. Hyphy? Hyph? AI. And it is the one that you wear in your pocket and it can detect the coughing all day and then send alerts into the healthcare workers. It's said to be very good. It then is feeding into metadata sets. It should feed into hotspot and geolocation apps as well, shouldn't it? And so the vision is that you can identify illness and track health through these mobile apps. Let me move on quickly. Wound care AI. Have you all seen this? Right? This is super cool. So lots of different apps and processes for doing wound care with artificial intelligence. And why am I bringing this up? Because somebody here is either gonna get rich because of this slide or better yet, engage me in this effort and then we'll get rich together. Okay, so machine learning is great for what? It's great for repetitive processes like looking at a chest x-ray, right? Something that you're doing the same thing over and over and over to come to a fixed outcome, right? So what they do, what they show in this study is that wound analysis is on par with pathologists in analyzing image-based data. The computer, what they use is LIDAR, right? The laser image detection and recognition, which is on, by the way, I think all of your new iPhones, not mine, it's old, but they have them. So here's our opportunity. And I looked for this, Ken, and I don't know if you've seen this, but I searched. Why don't we have a skin test reader using LIDAR, right? Thank you. We'll partner up after this. Why, we all know that people reading skin tests is full of flaws, right? But you could LIDAR it because it can get you the 3D dimension using LIDAR. So you're not gonna make a mistake getting a red spot and measuring it wrong. It's gonna be measured automatically by the app. It'll measure the height. You can do it on any darkness of skin because sometimes that's one of the problems people have. And so I think this is an incredible opportunity. Why couldn't it accurately interpret a skin test? I think artificial intelligence in this case could lower human error, reduce healthcare worker workload. Why do we need to have healthcare workers placing and reading and placing and reading and going out to the workplace? Kaiser, California, because California still requires it. My husband drives 30 minutes in as an ER doc to have his TST read and then drives back home. It's a giant waste of time. Look, this isn't as good for the lesser developed countries, but it's great for the more developed countries. And then you could scale up and have this LTBI evaluation with automated reporting and the hotspots and everything. So I thought that was pretty cool. Okay, deep learning is here. So deep learning is a subcategory of machine learning that learns to identify patterns and images. You can do this with chest X-rays. As I mentioned, I showed you the cough one. I won't go through this, but here's the validation on that study that you can look at yourself, where they trained, how they trained, and this is through Stanford, and I see Dr. Bowman here, how they trained the machine to read these x-rays. And the best performance came actually when they combined two different sort of AI networks using AlexNet and GoogleNet, and that statistically combined, and I don't know why it's off the screen, but it was like 97%. So we could have chest x-rays, and look at this for lesser developed countries, right? If we could have community health workers or these small places have chest x-rays automatically read instead of by the very rare to find radiologist, right, who doesn't have the time to read a million chest x-rays and may not be as good. Well, yes, here's the company that did this. QXR, this comes out of India. This is Cure AI. In less than one minute, the phone or computer app can scan the x-ray for TB, COVID-19, and 27 other conditions. If there's evidence of TB, a patient risk score is assigned. And then studies in this one comparing the AI applications by the Stop TB Partnership found that all of the AI apps, all of the AI apps outperformed experienced human readers. QXR seemed to be the best of the apps there was. Okay, are you thinking this is cool? I know it's a little disorganized today, but I'm gonna keep going then. Okay, real quick, genomics and AI, what else has happened in the last two years? Have you ever heard of these, of cell-free, I'm sorry that the slides are goofed up, that this detects microbial cell-free DNA? Have you heard of this? So when somebody has an infection, that pathogen will die somewhere in their system and it will release these microparticles of DNA. Now that we can do so much whole genome sequencing in the human, and we've got genetic sequencing of all these viruses, you can actually pick up, they can pick up, these micro cell-free DNA that are floating around in blood and identify this company Karius says 1,000 different pathogens. I was pretty skeptical because I work about a block from Theranos. I was told to be very careful when I said that. But I've checked with multiple people about Karius and they seem to really be onto something. This is a test that you drop in, send to them overnight. They can run in an hour and a half and give you the results. They are using it right now actively, but only for very sick people. I think the volume then of the pathogen is higher. And what's on their list of 1,000 pathogens? There we have it. Not only tuberculosis, but NTMs, which causes a great problem, right, in the diagnosis. Okay, digital pathology. So we talked a little bit about lesion recognition, using LIDAR. Pathologists are great. They did this for TB quite a while ago, actually. Most TB, where's the year? 2020 and 2018. So they took lung pathology, examined it, double-confirmed diagnosis by pathologies using microscopes and digital slides. And the AI pathologist did as well or better than the pathologist. So digital pathology. This is really cool. You wanna treat people and you wanna know whether they got treated or not? Use a smart pillbox. So they're distributing these in lesser-developed countries. Thank you. Almost done. They're delivering these smart pillboxes. So you open it up and it reminds patients to take pills with lights. It informs the healthcare worker if they don't take the pill out of the pocket. It sends a notice to them at the end of the day, like a text. And when they deliver these, they have a battery, a chip, a charger. It comes with a three-year plan with a SIM card. This is another product that's being given out to communities to stay in that community. The intention is for about three years. It has an app inside this that gives video DOT also. So you can watch people taking their medicines. They did an initial study with 3,000 people. Their secondary study is going on now with 10,000 people. Unfortunately, one of those sites was Ukraine. Okay, last, gene therapy. There is actually really cool studies where they found that some of the really slow uptake of medications, and particularly with tuberculosis, is that TB runs in two phases. So it kind of wakes up initially, and then there's the slow, like, quiescent phase, and it wakes up again later. It's part of why, apparently, we have to treat it for so long. And so this gene mutation was recognized and was effectively knocked out in one colony of mice, I believe. Rapidly correcting frame shift mutations. So this is very interesting in longer slides. I don't want to spend long on the mRNA, but I knew everybody would want to know why don't we have an mRNA vaccine for TB? I don't know if Dr. Castro can answer that. But there was one. So this is kind of cool. In 2004, there was an mRNA vaccine shown to protect mice against TB for greater than 15 years. I'm sorry, greater than 15 years ago. And it served as a proof of concept for the current COVID-19 vaccines. Here's the study. It was four injections every three weeks. The thing is, mRNA is expensive to make. Right now, it requires cold chain. You would have to figure out how to make, the costs have dropped dramatically in COVID, but you'd have to figure out how to do it in, like, a freeze-dried, stable way so that it didn't have to be delivered in cold chain. But I think it can be done technologically. Okay, last cool intervention, because this one's super cool. Okay, so there's this new vaccine delivery system of 3D-printed vaccines. Have you ever seen this? Okay, so multiple companies are doing this now. Transdermal vaccination using 3D-printed micro-needles. You see with the finger and with that little tiny Band-Aid the size of these. This is all proved and all validated, okay? You 3D-print the little needles. The vaccine is in there. You can send these to people's homes. This was being worked on for COVID in that little packet, and people can self-vaccinate. So imagine the future of vaccine distribution if we can really make this work on a large scale. This is published in 2021. These companies exist. They're presenting at TEDx. They're validated, and I think this is really cool, and I am done. So what do we need to do? In the United States, we know where LTBI is. We know that it's in the foreign-born and in a couple of these hotspot states, Florida, Texas, California, Alaska, and Hawaii. We have the means to treat it. So let's test with IGRAs. Let's use our short-course treatments, and let's eliminate TB in the U.S. I'll skip all that. Actually, I won't. Decreasing worldwide TB was slow. It made some progress in the last 130 years, but the COVID-19 pandemic that set us back could be a way that we leapfrog into the future, and we skip, just like Elon Musk did, putting these satellites up into the orbit. Why don't we skip all the low-level things, leapfrog to solar power, to artificial intelligence and genomics and digital pathology, and move forward with our tuberculosis? I think the future could be very, very bright. A nod to Paul Farmer, who we lost this year, one of our great heroes. He says, the well should take care of the sick, and all of you are doing that right now. Thank you so very much. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. All right. You talked about the dose response effect from the bird, ship, TB exposure. There've been a couple of papers, Zhang and other people have said there is a dose response with COVID, and some papers have said there's not, there's more of a threshold effect. What is your opinion? I think we remain by and large ignorant. We haven't looked with the tenacity that it takes and repetitively, because one study will show you something, but it should be confirmed by other subsequent studies. Given the airborne nature of the pathogen, I think it makes intuitive sense to think that it's gonna behave very similarly, that there will be a dose response effect also, and that duration of exposure will also play a factor. I mean, having me whisked by someone who's contagious is not gonna be the same as if I sit and eat with that person for a prolonged period of time. By the way, the other thing that I will digress in responding to your question, we've learned is that in the case of tuberculosis, when people have a TB of the larynx and vocal cord, they're highly contagious because then they are aerosolizing these, and I wonder to what extent could we see something like that? Omicron wave, I had a mildly symptomatic case in late December, and it was mostly a sore throat and coughing, no fever or anything else, and I suspect that I might have been a lot more contagious during that time than otherwise. But getting back to your answer, I don't think we know yet, but intuitively, I think there will be a dose response to be demonstrated. Thank you. Thank you all for your wonderful presentations. I missed the beginning of Dr. Castro's presentation, so I apologize if my question is going to be a reflection of what you said before, but my understanding is we are never gonna get a jump on TB unless we have vaccines, and Wendy referred to it at the very end, but I don't think anybody has talked yet here today about a vaccine to prevent people who have latent TB from developing active TB, similar to Shingrix. Could somebody talk about that, please? Yes, there are a couple of vaccine candidates that have established a proof of concept that are in phase two trials. We need the phase three trials, and it's also looking at blocking deceased progression among the universe of latently infected. In fact, I would argue that in a place like the United States of America, where you have about 13 million latently infected persons, that's a vaccine that's gonna be of interest to us, not a vaccine that prevents infection because the universe of new infections in the United States is lower. So the other thing I will say, and pardon me for sounding crass, we're paying for the consequences of long-term disinvestment in tuberculosis research. I'm gonna just add to that. What I should have said is that all of the things that I presented are because we had a brain trust, and we had a financial trust. The entire world came together and did an amazing job at tackling COVID. It was incredible, and I wanna use those things to leapfrog us in TB. There are 21 vaccines in the pipeline. I cut that slide. The R121 is the one that the WHO has recommended officially. I believe it was just past phase two. I don't know that it's being, I think it's just in its phase three, but it's officially- And these are secondary prevention. That's a prevention. Secondary prevention for latent TB. No, this is just a vaccine. This is a primary. It's the R121, and that one has already, I think, been supplanted by data from another R number that looks like it's even better. So there are vaccines. There's 21 in the pipeline that I saw. I cut that slide. But for that transition that you mentioned, Gwen, I think that would be amazing. That's what we need. Thank you. Dr. Swift. Thank you so much. So my question's for Dr. Higashi. So previously, our exposure risk assessment in the occupational realm in healthcare was kind of a trade secret and a bit of judgment. And what COVID did, I think, was raise the profile of the importance of an exposure risk assessment that's consistent because now we had to apply it to hundreds of healthcare workers all day long. And the duration of exposure sort of varied, five minutes, a few minutes, 15, 15 minutes cumulatively. We know it's a continuum. We know we're just making a risk assessment here. But it did help to sort of help us create algorithms, decide exposure in, exposure out, where are we gonna put our resources, right? So having spent half a day last week with a new ID staff physician, gently suggesting that perhaps a three-minute masked encounter across a registration desk did not constitute a significant risk, occupational exposure, and struggling with that because A, we really have never put a time definition for the occupational exposure. And we struggled with that in the companion document. And B, much of our exposure risk experience is pre-COVID without universal source control. And so when you made your comment about the eight hours cumulatively over a week as a threshold and knowing like FAA uses, I think, four hours of airplane exposure before contacts are notified for TB, what are your thoughts about the occupational assessment, that risk assessment of exposure for TB? And where should that threshold be now in 2022? Yeah, that's a great question. We had concentrated some of our investigations during COVID in LA County to focus on health setting exposures with understanding that people were wearing different PPE. And so we haven't seen a lot of transmission because people have been wearing PPE. So our threshold is no different for it's eight hours cumulative exposure, but there are some situations where you would say, okay, we're in an infusions center with a lot of immunocompromised people. That's gonna change things a little bit. But for your routine sort of occupational health exposure, we're still sticking to that eight hours in the airspace of unprotected without PPE. And so N95, you got an N95 and you really didn't, you took your air, your break, and it wasn't, it didn't add up to eight hours. We're not recommending that you were potentially exposed. So we've done a lot of funneling down. Maybe we should publish some of this stuff. But honestly, that's kind of where we're at because we just simply had to prioritize. So we can then go back and say, this is a lower risk exposure. These are the things you consider. You might wanna opt in and maybe there's that person's immunocompromised so you wanna test them anyway, but that's what we're trying to do. But I think it's a good idea. And I think this sort of exposure threshold is a good way to kind of like at least assess what transmission risks are going forward. Thank you. It's a voice of sanity. Just to add something to, I fully agree with what you heard from Dr. Higashi. What I would also add is the exposed individual, if it's someone who's immunocompromised and has a high consequence of a bad outcome, you also wanna lower your threshold and go after them. It's a renal transplant on cytotoxic therapy. I would be more likely want to have that investigation take place. But if you have mostly healthy exposed individuals, the index case has minimal disease, they were wearing masks, et cetera, don't waste your time. Yeah, I mean, the situations where we'll have a two hour kind of exposure is the setting is an infusion center, HIV AIDS clinic, and those are for the people in the waiting room. But again, there's a lot of room for judgment. So that work with your local program, nobody's doing this in a standardized way right now, but we hope that's gonna change. Thank you. This is a question about the particle size distribution and its significance for prevention. For instance, Dr. Castro, you pointed out your laryngitis, et cetera. Do we think that the particle size for TB, SARS-CoV-1, two, MERS, they're all the same or are they different? Do you think Richard Riley's work, everybody quoted and delayed protection against small aerosols for a long time, with COVID for months, do you think that that's really valid? And then the implication for Dr. Thanasi in the future, and Dr. Ghoshy for control, is if control and prevention is ventilation and maybe UVGI and all that, do you think OSHA should talk about ventilation prevention just as they require it for ventilation against silicosis, et cetera, et cetera? Short answer is yes. Uppercase, all three letters. Yes, and thank you for bringing Richard Riley's work. We learned a lot through those type of experiments. What matters are these airborne droplet nuclei that remain suspended in air. Pardon me again for being so gross, that if I sneeze and there's a snot that falls on the floor, that composes no threat to anyone else. It's the particles that remain suspended. And there again, we need to look at SARS-CoV-2 and we haven't. In fact, for months, I kept being flustered with what I perceived to be in the early stages of the COVID pandemic, undue attention to hand washing and zero attention to airborne prevention. But I fully agree with you. And in fact, following up on Dr. Tanasi's mention that we now have a new way of thinking. We've been exposed to the COVID pandemic and what we didn't use to pay attention to is very much in our sense of awareness and we're more likely to act on that. And we need to take advantage of that. I do have a slide in other presentations where I quote Sir Winston Churchill, never let the crisis go to waste. People call that hygiene theater. Thank you for that. I'm stepping into Dr. Castro's airspace. Thank you for spending your morning with us. Thank you for coming so early. I should have said that. I should have said that much earlier. Thank you all.

latent tuberculosis

active tuberculosis

workplace

treatment

2019 guidance

testing

healthcare workers

incidence

companion document

operational guidance

transmission

screening

treatment options